Epigenetic editing was used to reduce the activity of a gene that affects cholesterol levels without changing the DNA sequence — and did so for an extended period, according to a study in mice by Cappelluti and colleagues. The study lays the foundation for the development of in vivo therapeutics that are based on epigenetic silencing. …
Cappelluti, M.A., Mollica Poeta, V., Valsoni, S. et al. Durable and efficient gene silencing in vivo by hit-and-run epigenome editing. Nature (2024). https://doi.org/10.1038/s41586-024-07087-8
Ueda J, Yamazaki T, Funakoshi H. Toward the Development of Epigenome Editing-Based Therapeutics: Potentials and Challenges. Int J Mol Sci. 2023 Mar 1;24(5):4778. doi: 10.3390/ijms24054778. PMID: 36902207; PMCID: PMC10003136.
T cells that are specific for B cells infected with Epstein–Barr virus (EBV) are enriched in the cerebrospinal fluid (CSF) of people with early multiple sclerosis (MS), according to new research. The finding adds to evidence that EBV has a role in the pathogenesis of MS, and offers insight into possible mechanisms.
Fyfe, I. T cells implicate Epstein–Barr virus in multiple sclerosis pathogenesis. Nat Rev Neurol (2024). https://doi.org/10.1038/s41582-024-00939-x
PARIS — Cancer and tobacco are a dangerous combination. This adage holds particularly true for cervical cancer, which is induced by high-risk human papillomavirus(HPV). Julia Maruani, MD, a gynecologist in Marseille, France, described this association during a press conference at the French Society of Colposcopy and Cervico-Vaginal Pathology Congress.
4500 Chemical Compounds
To clarify the role of tobacco in cervical cancer, Maruani observed that cigarettes contain nearly 4500 chemical compounds, 60 of which are carcinogenic. “For example, we know that benzopyrene increases viral load, while nitrosamines have a carcinogenic effect,” she said. “And don’t believe that nicotine has no impact. While not directly affecting carcinogenesis, it plays a harmful role in terms of immunosuppression. Tobacco alters all components of immunity: Cellular, humoral, local, and systemic.”
Indeed, tobacco is the leading modifiable risk factor for cancers, contributing to 13% of all cases. When considering cervical cancer in women, tobacco and HPV are the main risk factors. The same applies to cancers of the pharynx and nasopharynx. “There is an extremely strong association between cancer and tobacco for all sites affected by HPV infection,” said Maruani. …”
Food allergies are common and are associated with substantial morbidity; the only approved treatment is oral immunotherapy for peanut allergy.
METHODS
In this trial, we assessed whether omalizumab, a monoclonal anti-IgE antibody, would be effective and safe as monotherapy in patients with multiple food allergies. Persons 1 to 55 years of age who were allergic to peanuts and at least two other trial-specified foods (cashew, milk, egg, walnut, wheat, and hazelnut) were screened. Inclusion required a reaction to a food challenge of 100 mg or less of peanut protein and 300 mg or less of the two other foods. Participants were randomly assigned, in a 2:1 ratio, to receive omalizumab or placebo administered subcutaneously (with the dose based on weight and IgE levels) every 2 to 4 weeks for 16 to 20 weeks, after which the challenges were repeated. The primary end point was ingestion of peanut protein in a single dose of 600 mg or more without dose-limiting symptoms. The three key secondary end points were the consumption of cashew, of milk, and of egg in single doses of at least 1000 mg each without dose-limiting symptoms. The first 60 participants (59 of whom were children or adolescents) who completed this first stage were enrolled in a 24-week open-label extension.
RESULTS
Of the 462 persons who were screened, 180 underwent randomization. The analysis population consisted of the 177 children and adolescents (1 to 17 years of age). A total of 79 of the 118 participants (67%) receiving omalizumab met the primary end-point criteria, as compared with 4 of the 59 participants (7%) receiving placebo (P<0.001). Results for the key secondary end points were consistent with those of the primary end point (cashew, 41% vs. 3%; milk, 66% vs. 10%; egg, 68% vs. 0%; P<0.001 for all comparisons). Safety end points did not differ between the groups, aside from more injection-site reactions in the omalizumab group.
CONCLUSIONS
In persons as young as 1 year of age with multiple food allergies, omalizumab treatment for 16 weeks was superior to placebo in increasing the reaction threshold for peanut and other common food allergens. (Funded by the National Institute of Allergy and Infectious Diseases and others; ClinicalTrials.gov number, NCT03881696. opens in new tab.)
Wood RA et al., Omalizumab for the Treatment of Multiple Food Allergies. New England J. Med. , DOI: 10.1056/NEJMoa2312382. (2024).
Significance In the midst of rapid globalization, the peaceful coexistence of cultures requires a deeper understanding of the forces that compel prosocial behavior and thwart xenophobia. Yet, the conditions promoting such outgroup-directed altruism have not been determined. Here we report the results of a double-blind, placebo-controlled experiment showing that enhanced activity of the oxytocin system paired with charitable social cues can help counter the effects of xenophobia by fostering altruism toward refugees. These findings suggest that the combination of oxytocin and peer-derived altruistic norms reduces outgroup rejection even in the most selfish and xenophobic individuals, and thereby would be expected to increase the ease by which people adapt to rapidly changing social ecosystems.
Abstract Never before have individuals had to adapt to social environments defined by such magnitudes of ethnic diversity and cultural differentiation. However, neurobiological evidence informing about strategies to reduce xenophobic sentiment and foster altruistic cooperation with outsiders is scarce. In a series of experiments settled in the context of the current refugee crisis, we tested the propensity of 183 Caucasian participants to make donations to people in need, half of whom were refugees (outgroup) and half of whom were natives (ingroup). Participants scoring low on xenophobic attitudes exhibited an altruistic preference for the outgroup, which further increased after nasal delivery of the neuropeptide oxytocin. In contrast, participants with higher levels of xenophobia generally failed to exhibit enhanced altruism toward the outgroup. This tendency was only countered by pairing oxytocin with peer-derived altruistic norms, resulting in a 74% increase in refugee-directed donations. Collectively, these findings reveal the underlying sociobiological conditions associated with outgroup-directed altruism by showing that charitable social cues co-occurring with enhanced activity of the oxytocin system reduce the effects of xenophobia by facilitating prosocial behavior toward refugees.
Abstract: A 30-year-old woman presented with rapidly progressive dementia 1 month after the coronavirus disease 2019 infection. Repeated CSF analysis showed extreme hypoglycorrhachia, while cultures, metagenomic next-generation sequencing, and cytopathology testing of CSF were negative. Laboratory investigations for possible etiologies revealed elevated blood ammonia and cancer antigen 125. Brain MRI demonstrated bilateral symmetric diffuse cortical lesions with mild hyperintensity on T1-weighted image and postcontrast enhancement. A more thorough history and specific examinations subsequently indicated an underlying etiology. This case provides an approach for evaluating young patients with rapidly progressive dementia, extreme hypoglycorrhachia, and diffuse CNS lesions, highlighting the importance of considering a broad differential diagnosis.
Bai X, Xiang J, Deng J, Ding WH, Luan X, Geng Z. Clinical Reasoning: A 30-Year-Old Woman Presenting With Rapidly Progressive Dementia and Extreme Hypoglycorrhachia. Neurology. 2024 Mar 12;102(5):e209188. doi: 10.1212/WNL.0000000000209188. Epub 2024 Feb 5. PMID: 38315946.
“Neurologic damage following acute viral infections may be attributed to an excessive immune response to the infection, according to a new study.
Many viral infections that don’t directly infect the central nervous system (CNS) have been associated with severe neurologic disease. For these viruses, including newer viruses such as SARS-CoV-2 and Zika, the mechanism behind the association is poorly understood. To gain a better picture of how viruses may cause neurologic disease, researchers used a mouse model of Zika virus infection and identified a population of T cells that may be responsible for the damage.“ The study found that it isn’t the virus itself alone that causes the damage. Instead, it’s a very excessive immune response to the virus.
Balint, E., Feng, E., Giles, E.C. et al. Bystander activated CD8+ T cells mediate neuropathology during viral infection via antigen-independent cytotoxicity. Nat Commun15, 896 (2024). https://doi.org/10.1038/s41467-023-44667-0
“COVID-19 can cause long-term problems with thinking, concentrating, and remembering. This condition is commonly known as “brain fog.” Brain fog after COVID-19 has been studied mostly by observing previously healthy people.
In a small study supported by the National Institute of Neurological Disorders and Stroke (NINDS), researchers examined the cognitive impact of COVID-19 on people with dementia. The researchers found that having COVID-19 rapidly accelerated the structural and functional brain deterioration of patients with dementia, regardless of the type of dementia being experienced.………..
Researchers followed 14 patients with preexisting dementia who were already enrolled in an ongoing dementia study and who had COVID-19 while participating in the study. Among these patients, four had Alzheimer’s disease, five had vascular dementia, three had Parkinson’s disease dementia, and two had the behavioral variant of frontotemporal dementia.
The researchers tested various cognitive functions and conducted brain imaging, comparing results from assessments within three months before their cases of COVID-19 and then one year after infection.
A year after contracting COVID-19, all of the patients with dementia had experienced a significant increase in fatigue and depression, as well as worsening attention, memory, speech, visuospatial capabilities, and executive functions. All the patients also had cerebral atrophy, which is the loss of neurons and connections between neurons, and lesions deep in the white matter of their brains.
Despite having different types of dementia, these patients developed similar dementia symptoms after having COVID-19. Overall, these patients experienced rapid structural and functional brain deterioration after COVID-19 infection.
Based on the unique brain changes seen in these patients, the researchers proposed a new term to describe the brain complications associated with COVID-19 in people with dementia: FADE-IN MEMORY (Fatigue, decreased Fluency, Attention deficit, Depression, Executive dysfunction, slowed INformation processing speed, and subcortical MEMORY impairment).
Why is this research important?
This study shows that COVID-19 causes severe neurological complications in people with dementia. According to these results, COVID-19 appears to accelerate disease progression in all types of dementia. Further research is needed to understand why COVID-19 accelerates brain deterioration in patients with dementia. This research could also inform the development of treatments to slow the progression of dementia in patients who have had COVID-19.”
Dubey, S., Das, S., Ghosh, R., Dubey, M. J., Chakraborty, A. P., Roy, D., Das, G., Dutta, A., Santra, A., Sengupta, S., & Benito-León, J. (2023). The effects of SARS-CoV-2 infection on the cognitive functioning of patients with pre-existing dementia. Journal of Alzheimer’s Disease Reports, 7(1), 119–128. https://doi.org/10.3233/ADR-220090
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Three-dimensional printing technology, also called additive manufacturing technology, is used to prepare personalized 3D-printed drugs through computer-aided model design. In recent years, the use of 3D printing technology in the pharmaceutical field has become increasingly sophisticated. In addition to the successful commercialization of Spritam®in 2015, there has been a succession of Triastek’s 3D-printed drug applications that have received investigational new drug (IND) approval from the Food and Drug Administration (FDA). Compared with traditional drug preparation processes, 3D printing technology has significant advantages in personalized drug manufacturing, allowing easy manufacturing of preparations with complex structures or drug release behaviors and rapid manufacturing of small batches of drugs. This review summaries the mechanisms of the most commonly used 3D printing technologies, describes their characteristics, advantages, disadvantages, and applications in the pharmaceutical industry, analyzes the progress of global commercialization of 3D printed drugs and their problems and challenges, reflects the development trends of the 3D printed drug industry, and guides researchers engaged in 3D printed drugs.
Introduction:
In contrast to the traditional manufacturing techniques of “subtractive manufacturing”, 3D printing is an “additive manufacturing” technology, where a model is constructed using computer-aided design software, sliced, and transferred to a printer, and the 3D product is then constructed layer by layer using the principle of layered manufacturing [1,2]. With the research and development of 3D printing technology, many new 3D printing technologies have emerged one after another. As each 3D printing technology uses different materials, deposition techniques, layering manufacturing mechanisms, and final product characteristics, the American Society for Testing and Materials classified 3D printing technologies into seven categories according to their technical principles [3,4], namely material extrusion, binder jetting, powder bed fusion, vat photopolymerization, material jetting, directed energy deposition, and sheet lamination.
Three-dimensional printing technology is widely used in automotive, construction, aerospace, medical, and many other fields. In the pharmaceutical sector, research into 3D printing technology is currently experiencing a global boom [5,6]. Compared to traditional preparation technologies, 3D printing offers flexibility in the design of complex 3D structures within drugs, the adjustment of drug doses and combinations, and rapid manufacturing and prototyping, enabling precise control of drug release to meet a wide range of clinical needs, a high degree of flexibility and creativity to personalize pharmaceuticals, and a significant reduction in preparation development time, driving a breakthrough in drug manufacturing technology and transforming the way we design, manufacture, and use drugs [7,8,9]. Three-dimensional printing technologies have been used to manufacture a variety of medicinal products, such as immediate-release tablets, controlled-release tablets, dispersible films, microneedles, implants, and transdermal patches [10]. The main 3D printing technologies used in pharmaceuticals are BJ-3DP, FDM, SSE, and MED in material extrusion, and SLA [11]. Table 1 describes the characteristics of these technologies at each stage of drug preparation and assesses the advantages and disadvantages of each technology. …”
Wang S, Chen X, Han X, Hong X, Li X, Zhang H, Li M, Wang Z, Zheng A. A Review of 3D Printing Technology in Pharmaceutics: Technology and Applications, Now and Future. Pharmaceutics. 2023 Jan 26;15(2):416. doi: 10.3390/pharmaceutics15020416. PMID: 36839738; PMCID: PMC9962448.
This study explores the innovative production of personalized bilayer tablets, integrating two advanced manufacturing techniques: Droplet Deposition Modeling (DDM) and Injection Molding (IM). Unlike traditional methods limited to customizing dense bilayer medicines, our approach uses Additive Manufacturing (AM) to effectively adjust drug release profiles. Focusing on Caffeine and Paracetamol, we found successful processing for both DDM and IM using Caffeine formulation. The high viscosity of Paracetamol formulation posed challenges during DDM processing. Integrating Paracetamol formulation for the over-molding process proved effective, demonstrating IM’s versatility in handling complex formulations. Varying infill percentages in DDM tablets led to distinct porosities affecting diverse drug release profiles in DDM-fabricated tablets. In contrast, tablets with high-density structures formed through the over-molding process displayed slower and more uniform release patterns. Combining DDM and IM techniques allows for overcoming the inherent limitations of each technique independently, enabling the production of bilayer tablets with customizable drug release profiles. The study’s results offer promising insights into the future of personalized medicine, suggesting new pathways for the development of customized oral dosage forms.
Ebrahimi F, Xu H, Fuenmayor E, Major I. Tailoring drug release in bilayer tablets through droplet deposition modeling and injection molding. Int J Pharm. 2024 Jan 31:123859. doi: 10.1016/j.ijpharm.2024.123859. Epub ahead of print. PMID: 38307401.
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