Molecular Aspects of Medicine最新文献

The growing pool of critically ill or immunocompromised patients leads to a constant increase of life-threatening invasive infections by fungi such as Aspergillus spp., Candida spp. and Pneumocystis jirovecii.

In response to this, prophylactic and pre-emptive antifungal treatment strategies have been developed and implemented for high-risk patient populations. The benefit by risk reduction needs to be carefully weighed against potential harm caused by prolonged exposure against antifungal agents. This includes adverse effects and development of resistance as well as costs for the healthcare system.

In this review, we summarise evidence and discuss advantages and downsides of antifungal prophylaxis and pre-emptive treatment in the setting of malignancies such as acute leukaemia, haematopoietic stem cell transplantation, CAR-T cell therapy, and solid organ transplant. We also address preventive strategies in patients after abdominal surgery and with viral pneumonia as well as individuals with inherited immunodeficiencies.

Notable progress has been made in haematology research, where strong recommendations regarding antifungal prophylaxis and pre-emptive treatment are backed by data from randomized controlled trials, whereas other critical areas still lack high-quality evidence. In these areas, paucity of definitive data translates into centre-specific strategies that are based on interpretation of available data, local expertise, and epidemiology.

The development of novel immunomodulating anticancer drugs, high-end intensive care treatment and the development of new antifungals with new modes of action, adverse effects and routes of administration will have implications on future prophylactic and pre-emptive approaches.

Cancer prevention is one of the aim with the highest priority in order to reduce the burden of cancer diagnosis and treatment on individuals as well as on healthcare systems.

To this aim, vaccines represent the most efficient primary cancer prevention strategy. Indeed, anti-cancer immunological memory elicited by preventive vaccines might promptly expand and prevent tumor from progressing.

Antigens derived from microorganisms (MoAs), represent the obvious target for developing highly effective preventive vaccines for virus-induced cancers. In this respect, the drastic reduction in cancer incidence following HBV and HPV preventive vaccines are the paradigmatic example of such evidence. More recently, experimental evidences suggest that MoAs may represent a “natural” anti-cancer preventive vaccination or can be exploited for developing vaccines to prevent cancers presenting highly homologous tumor-associated antigens (TAAs) (e.g. molecular mimicry).

The present review describes the different preventive anti-cancer vaccines based on antigens derived from pathogens at the different stages of development.

The gram-negative bacterium Helicobacter pylori is the most common chronic bacterial infection and the main cause of gastric cancer. Due to the increasing antimicrobial resistance of H. pylori, the development of an efficacious vaccine is a valid option to protect from disease or infection and ultimately prevent gastric cancer. However, despite more than 30 years of research, no vaccine has entered the market yet. This review highlights the most relevant previous preclinical and clinical studies to allow conclusions to be drawn on which parameters need special attention in the future to develop an efficacious vaccine against H. pylori and thus prevent gastric cancer.

With more than 5 million fatalities and close to 300 million reported cases, COVID-19 is the first documented pandemic due to a coronavirus that continues to be a major health challenge. Despite being rapid, uncontrollable, and highly infectious in its spread, it also created incentives for technology development and redefined public health needs and research agendas to fast-track innovations to be translated. Breakthroughs in computational biology peaked during the pandemic with renewed attention to making all cutting-edge technology deliver agents to combat the disease. The demand to develop effective treatments yielded surprising collaborations from previously segregated fields of science and technology. The long-standing pharmaceutical industry's aversion to repurposing existing drugs due to a lack of exponential financial gain was overrun by the health crisis and pressures created by front-line researchers and providers. Effective vaccine development even at an unprecedented pace took more than a year to develop and commence trials. Now the emergence of variants and waning protections during the booster shots is resulting in breakthrough infections that continue to strain health care systems. As of now, every protein of SARS-CoV-2 has been structurally characterized and related host pathways have been extensively mapped out. The research community has addressed the druggability of a multitude of possible targets. This has been made possible due to existing technology for virtual computer-assisted drug development as well as new tools and technologies such as artificial intelligence to deliver new leads. Here in this article, we are discussing advances in the drug discovery field related to target-based drug discovery and exploring the implications of known target-specific agents on COVID-19 therapeutic management. The current scenario calls for more personalized medicine efforts and stratifying patient populations early on for their need for different combinations of prognosis-specific therapeutics. We intend to highlight target hotspots and their potential agents, with the ultimate goal of using rational design of new therapeutics to not only end this pandemic but also uncover a generalizable platform for use in future pandemics.

The field of precision medicine allows for tailor-made treatments specific to a patient and thereby improve the efficiency and accuracy of disease prevention, diagnosis, and treatment and at the same time would reduce the cost, redundant treatment, and side effects of current treatments. Here, the combination of organ-on-a-chip and bioprinting into engineering high-content in vitro tissue models is envisioned to address some precision medicine challenges. This strategy could be employed to tackle the current coronavirus disease 2019 (COVID-19), which has made a significant impact and paradigm shift in our society. Nevertheless, despite that vaccines against COVID-19 have been successfully developed and vaccination programs are already being deployed worldwide, it will likely require some time before it is available to everyone. Furthermore, there are still some uncertainties and lack of a full understanding of the virus as demonstrated in the high number new mutations arising worldwide and reinfections of already vaccinated individuals. To this end, efficient diagnostic tools and treatments are still urgently needed. In this context, the convergence of bioprinting and organ-on-a-chip technologies, either used alone or in combination, could possibly function as a prominent tool in addressing the current pandemic. This could enable facile advances of important tools, diagnostics, and better physiologically representative in vitro models specific to individuals allowing for faster and more accurate screening of therapeutics evaluating their efficacy and toxicity. This review will cover such technological advances and highlight what is needed for the field to mature for tackling the various needs for current and future pandemics as well as their relevancy towards precision medicine.

Topics expected to influence personalized medicine (PM), where medical decisions, practices, and treatments are tailored to the individual patient, are reviewed. Lack of discrimination due to different biological conditions that express similar values of numerical variables (ambiguity) is regarded to be a major potential barrier for PM. This material explores possible causes and sources of ambiguity and offers suggestions for mitigating the impacts of uncertainties.

Three causes of ambiguity are identified: (1) delayed adoption of innovations, (2) inadequate emphases, and (3) inadequate processes used when new medical practices are developed and validated. One example of the first problem is the relative lack of medical research on “compositional data” –the type that characterizes leukocyte data. This omission results in erroneous use of data abundantly utilized in medicine, such as the blood cell differential. Emphasis on data output ‒not biomedical interpretation that facilitates the use of clinical data‒ exemplifies the second type of problems. Reliance on tools generated in other fields (but not validated within biomedical contexts) describes the last limitation.

Because reductionism is associated with these problems, non-reductionist alternatives are reviewed as potential remedies. Data structuring (converting data into information) is considered a key element that may promote PM. To illustrate a process that includes data-information-knowledge and decision-making, previously published data on COVID-19 are utilized.

It is suggested that ambiguity may be prevented or ameliorated. Provided that validations are grounded on biomedical knowledge, approaches that describe certain criteria – such as non-overlapping data intervals of patients that experience different outcomes, immunologically interpretable data, and distinct graphic patterns – can inform, at personalized bases, earlier and/or with fewer observations.

A variety of technologies are emerging to help clinicians provide patient-specific diagnosis and therapies. This special edition of the Molecular Aspects of Medicine is a collection of mini reviews covering a broad range of topics, from systems to model patient variants and discover therapies (Microphysiological systems with patient derived tissue and CRISPR-humanized animal models), to new modalities in diagnostics and therapeutics (Extracellular Vesicles, RNA therapeutics, microbiome and molecular dynamics).

Extracellular vesicles (EVs) are released from all cells in the body, forming an important intercellular communication network that contributes to health and disease. The contents of EVs are cell source-specific, inducing distinct signaling responses in recipient cells. The specificity of EVs and their accumulation in fluid spaces that are accessible for liquid biopsies make them highly attractive as potential biomarkers and therapies for disease. The duality of EVs as favorable (therapeutic) or unfavorable (pathological) messengers is context dependent and remains to be fully determined in homeostasis and various disease states. This review describes the use of EVs as biomarkers, drug delivery vehicles, and regenerative therapeutics, highlighting examples involving viral infections, cancer, and neurological diseases. There is growing interest to provide personalized therapy based on individual patient and disease characteristics. Increasing evidence suggests that EV biomarkers and therapeutic approaches are ideal for personalized medicine due to the diversity and multifunctionality of EVs.

Certain genetic variants underlie the proper functioning of the nervous system. They affect the nervous system in all aspects - molecular, systemic, cognitive, computational and sensorimotor. The greatest changes in the nervous system take place in the process of its maturation in the period of psychomotor development, as well as during neurorehabilitation, the task of which is to rebuild damaged neuronal pathways, e.g. by facilitating movement or training cognitive functions. Certain genetic polymorphisms affect the effectiveness of the processes of reconstruction or restoration of neural structures, which is clearly reflected in the effects of neurorehabilitation. This review presents the perspectives for the application of neurogenetic research in programming neurorehabilitation by determining the relationship of as many as 16 different genetic polymorphisms with specific functions of importance in rehabilitation. Thanks to this broad view, it may be possible to predict the effectiveness of rehabilitation on the basis of genetic testing, which would significantly contribute to the development of personalized medicine and to the optimal management of medical services in healthcare systems.

Advances in genome sequencing have greatly facilitated the identification of genomic variants underlying rare neurodevelopmental and neurodegenerative disorders. Understanding the fundamental causes of rare monogenic disorders has made gene therapy a possible treatment approach for these conditions. RNA interference (RNAi) technologies such as small interfering RNA (siRNA), microRNA (miRNA), and short hairpin RNA (shRNA), and other oligonucleotide-based modalities such as antisense oligonucleotides (ASOs) are being developed as potential therapeutic approaches for manipulating expression of the genes that cause a variety of neurological diseases. Here, we offer a brief review of the mechanism of action of these RNAi approaches; provide deeper discussion of the advantages, challenges, and specific considerations related to the development of RNAi therapeutics for neurological disease; and highlight examples of rare neurological diseases for which RNAi therapeutics hold great promise.