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Research conducted on the International Space Station (ISS) in low-Earth orbit (LEO) has shown the effects of microgravity on multiple organs. To investigate the effects of microgravity on the central nervous system, we developed a unique organoid strategy for modeling specific regions of the brain that are affected by neurodegenerative diseases. We generated 3-dimensional human neural organoids from induced pluripotent stem cells (iPSCs) derived from individuals affected by primary progressive multiple sclerosis (PPMS) or Parkinson's disease (PD) and non-symptomatic controls, by differentiating them toward cortical and dopaminergic fates, respectively, and combined them with isogenic microglia. The organoids were cultured for a month using a novel sealed cryovial culture method on the International Space Station (ISS) and a parallel set that remained on Earth. Live samples were returned to Earth for analysis by RNA expression and histology and were attached to culture dishes to enable neurite outgrowth. Our results show that both cortical and dopaminergic organoids cultured in LEO had lower levels of genes associated with cell proliferation and higher levels of maturation-associated genes, suggesting that the cells matured more quickly in LEO. This study is continuing with several more missions in order to understand the mechanisms underlying accelerated maturation and to investigate other neurological diseases. Our goal is to make use of the opportunity to study neural cells in LEO to better understand and treat neurodegenerative disease on Earth and to help ameliorate potentially adverse neurological effects of space travel., (© The Author(s) 2024. Published by Oxford University Press.)

In extreme environments people will have different needs for medicine(s), making it crucial to understand how such environments affect drug efficacy. Ibuprofen, commonly used in tablet formulation on Earth, could fail in space despite standard pharmaceutical packaging. We introduce the concept of 'space medicines', where solid-dosage forms protect the pharmaceutical from accelerated degradation in spaceflight. We simulate dose(s) in International Space Station (ISS) through radionuclide and photon experiments, and establish the impact of alpha, beta and gamma rays. We demonstrate that tablet formulation protects from impact of alpha and beta rays; however, gamma rays decompose ibuprofen even when 'masked'. We systematically analyse 19 tablet compositions inside and outside the ISS to determine the effect of compositional changes in the tablet matrix. We confirm that the iron oxide-shielded tablets show minimal degradation (〈10%) inside the ISS, compared to moderate reductions (〉10%) for other formulations, with one exception. The tablets exhibited significantly greater ibuprofen degradation (〉 30-50%) outside ISS, due to harsh conditions. Significantly, we found that flavour have shielding potential by scavenging free radicals. We conclude that ibuprofen efficacy is adversely affected in space, and these effects are expected to worsen on missions to deeper space destinations., (© 2024 Wiley‐VCH GmbH.)

Low Earth Orbit (LEO) has emerged as a unique environment for evaluating altered stem cell properties in microgravity. LEO has become increasingly accessible for research and development due to progress in private spaceflight. Axiom Mission 2 (Ax-2) was launched as the second all-private astronaut mission to the International Space Station (ISS). Frozen human induced pluripotent stem cells (hiPSCs) expressing green fluorescent protein (GFP) under the SOX2 promoter, as well as fibroblasts differentiated from SOX2-GFP hiPSCs, were sent to the ISS. Astronauts then thawed and seeded both cell types into commercially available 96-well plates, which provided surface tension that reduced fluid movement out of individual wells and showed that hiPSCs or hiPSC-derived fibroblasts could survive either in suspension or attached to a Matrigel substrate. Furthermore, both cell types could be transfected with red fluorescent protein (RFP)-expressing plasmid. We demonstrate that hiPSCs and hiPSC-fibroblasts can be thawed in microgravity in off-the-shelf, commercially-available cell culture hardware, can associate into 3D spheroids or grow adherently in Matrigel, and can be transfected with DNA. This lays the groundwork for future biomanufacturing experiments in space., (© 2024. The Author(s).)

Recent findings from studies involving astronauts and animal models indicate that microgravity increases immune cell activity and potentially alters the white and gray matter of the central nervous system (CNS). To further investigate the impact of microgravity on CNS cells, we established cultures of three-dimensional neural organoids containing isogenic microglia, the brain's resident immune cells, and sent them onboard the International Space Station. When using induced pluripotent stem cell (iPSC) lines from individuals affected by neuroinflammatory and neurodegenerative diseases such as multiple sclerosis (MS) and Parkinson's disease (PD), these cultures can provide novel insights into pathogenic pathways that may be exacerbated by microgravity. We have devised a cryovial culture strategy that enables organoids to be maintained through space travel and onboard the International Space Station (ISS) without the need for medium or carbon dioxide exchange. Here, we provide a comprehensive description of all the steps involved: generating various types of neural organoids, establishing long-term cultures, arranging plans for shipment to the Kennedy Space Center (KSC), and ultimately preparing organoids for launch into low-Earth orbit (LEO) and return to Earth for post-flight analyses., (© 2024. Springer Science+Business Media, LLC.)

Transporting tissues and organs from the site of donation to the patient in need, while maintaining viability, is a limiting factor in transplantation medicine. One way in which the supply chain of organs for transplantation can be improved is to discover novel approaches and technologies that preserve the health of organs outside of the body. The dominant technologies that are currently in use in the supply chain for biological materials maintain tissue temperatures ranging from a controlled room temperature (+25 °C to +15 °C) to cryogenic (-120 °C to -196 °C) temperatures (reviewed in Criswell et al. Stem Cells Transl Med. 2022). However, there are many cells and tissues, as well as all major organs, that respond less robustly to preservation attempts, particularly when there is a need for transport over long distances that require more time. In this perspective article, we will highlight the current challenges and advances in biopreservation aimed at "freezing biological time," and discuss the future directions and requirements needed in the field., (© The Author(s) 2022. Published by Oxford University Press.)

The direct (eg, radiation, microgravity) and indirect (eg, lifestyle perturbations) effects of spaceflight extend across multiple systems resulting in whole-organism cardiovascular deconditioning. For over 50 years, National Aeronautics and Space Administration has continually enhanced a countermeasures program designed to characterize and offset the adverse cardiovascular consequences of spaceflight. In this review, we provide a historical overview of research evaluating the effects of spaceflight on cardiovascular health in astronauts and outline mechanisms underpinning spaceflight-related cardiovascular alterations. We also discuss how spaceflight could be leveraged for aging, industry, and model systems such as human induced pluripotent stem cell-derived cardiomyocytes, organoid, and organ-on-a-chip technologies. Finally, we outline the increasing opportunities for scientists and clinicians to engage in cardiovascular research in space and on Earth.

Advances in regenerative medicine manufacturing continue to be a priority for achieving the full commercial potential of important breakthrough therapies. Equally important will be the establishment of distribution chains that support the transport of live cells and engineered tissues and organs resulting from these advanced biomanufacturing processes. The importance of a well-managed distribution chain for products requiring specialized handling procedures was highlighted during the COVID-19 pandemic and serves as a reminder of the critical role of logistics and distribution in the success of breakthrough therapies. This perspective article will provide insight into current practices and future considerations for creating global distribution chains that facilitate the successful deployment of regenerative medicine therapies to the vast number of patients that would benefit from them worldwide., (© The Author(s) 2022. Published by Oxford University Press.)

Background: In this first-in-human, Phase 1 study of a microRNA-based cancer therapy, the recommended Phase 2 dose (RP2D) of MRX34, a liposomal mimic of microRNA-34a (miR-34a), was determined and evaluated in patients with advanced solid tumours., Methods: Adults with various solid tumours refractory to standard treatments were enrolled in 3 + 3 dose-escalation cohorts and, following RP2D determination, expansion cohorts. MRX34, with oral dexamethasone premedication, was given intravenously daily for 5 days in 3-week cycles., Results: Common all-cause adverse events observed in 85 patients enrolled included fever (% all grade/G3: 72/4), chills (53/14), fatigue (51/9), back/neck pain (36/5), nausea (36/1) and dyspnoea (25/4). The RP2D was 70 mg/m 2 for hepatocellular carcinoma (HCC) and 93 mg/m 2 for non-HCC cancers. Pharmacodynamic results showed delivery of miR-34a to tumours, and dose-dependent modulation of target gene expression in white blood cells. Three patients had PRs and 16 had SD lasting ≥4 cycles (median, 19 weeks, range, 11-55)., Conclusion: MRX34 treatment with dexamethasone premedication demonstrated a manageable toxicity profile in most patients and some clinical activity. Although the trial was closed early due to serious immune-mediated AEs that resulted in four patient deaths, dose-dependent modulation of relevant target genes provides proof-of-concept for miRNA-based cancer therapy., Clinical Trial Registration: NCT01829971.

Purpose Naturally occurring tumor suppressor microRNA-34a (miR-34a) downregulates the expression of >30 oncogenes across multiple oncogenic pathways, as well as genes involved in tumor immune evasion, but is lost or under-expressed in many malignancies. This first-in-human, phase I study assessed the maximum tolerated dose (MTD), safety, pharmacokinetics, and clinical activity of MRX34, a liposomal miR-34a mimic, in patients with advanced solid tumors. Patients and Methods Adult patients with solid tumors refractory to standard treatment were enrolled in a standard 3 + 3 dose escalation trial. MRX34 was given intravenously twice weekly (BIW) for three weeks in 4-week cycles. Results Forty-seven patients with various solid tumors, including hepatocellular carcinoma (HCC; n = 14), were enrolled. Median age was 60 years, median prior therapies was 4 (range, 1-12), and most were Caucasian (68%) and male (57%). Most common adverse events (AEs) included fever (all grade %/G3%: 64/2), fatigue (57/13), back pain (57/11), nausea (49/2), diarrhea (40/11), anorexia (36/4), and vomiting (34/4). Laboratory abnormalities included lymphopenia (G3%/G4%: 23/9), neutropenia (13/11), thrombocytopenia (17/0), increased AST (19/4), hyperglycemia (13/2), and hyponatremia (19/2). Dexamethasone premedication was required to manage infusion-related AEs. The MTD for non-HCC patients was 110 mg/m 2 , with two patients experiencing dose-limiting toxicities of G3 hypoxia and enteritis at 124 mg/m 2 . The half-life was >24 h, and C max and AUC increased with increasing dose. One patient with HCC achieved a prolonged confirmed PR lasting 48 weeks, and four patients experienced SD lasting ≥4 cycles. Conclusion MRX34 treatment with dexamethasone premedication was associated with acceptable safety and showed evidence of antitumor activity in a subset of patients with refractory advanced solid tumors. The MTD for the BIW schedule was 110 mg/m 2 for non-HCC and 93 mg/m2 for HCC patients. Additional dose schedules of MRX34 have been explored to improve tolerability.

High-grade serous ovarian cancer (HGSOC) is the most lethal form of gynecologic cancer, with limited treatment options and a poor prognosis. Epigenetic factors, such as microRNAs (miRNAs) and DNA methylation, play pivotal roles in cancer progression, yet their specific contributions to HGSOC remain insufficiently understood. In this study, we performed comprehensive high-throughput analyses to identify dysregulated miRNAs in HGSOC and investigate their epigenetic regulation. Analysis of tissue samples from advanced-stage HGSOC patients revealed 20 differentially expressed miRNAs, 11 of which were corroborated via RT-qPCR in patient samples and cancer cell lines. Among these, miR-145-3p was consistently downregulated post-neoadjuvant therapy and was able to distinguish tumoural from control tissues. Further investigation confirmed that DNA methylation controls MIR145 expression. Functional assays showed that overexpression of miR-145-3p significantly reduced cell migration and induced G0/G1 cell cycle arrest by modulating the cyclin D1-CDK4/6 pathway. These findings suggest that miR-145-3p downregulation enhances cell proliferation and motility in HGSOC, implicating its restoration as a potential therapeutic target focused on G1/S phase regulation in the treatment of HGSOC. [ABSTRACT FROM AUTHOR]

Simple Summary: Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease, affects over one billion adults worldwide. It can progress to more severe conditions, like metabolic dysfunction-associated steatohepatitis (MASH), cirrhosis, and hepatocellular carcinoma (HCC). Recent studies have highlighted the role of microRNAs (miRNAs) in this progression due to their ability to regulate genes involved in lipid metabolism, inflammation, fibrosis, and cell proliferation. Modulating miRNAs through synthetic molecules represents a promising therapeutic strategy. Preclinical models demonstrate that miRNA-based therapies can reduce liver inflammation and fibrosis and inhibit tumorigenesis, potentially delaying or preventing HCC onset. However, challenges such as delivery mechanisms, side effects, and long-term safety remain to be addressed. This review, focusing on recent preclinical and clinical studies, explores the pharmacological potential of miRNA-based interventions to counteract MASLD/MASH and their progression to HCC. It provides insights into an emerging field with significant implications for liver disease treatment. Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease (NAFLD), is a growing health concern worldwide, affecting more than 1 billion adults. It may progress to metabolic dysfunction-associated steatohepatitis (MASH), cirrhosis, and ultimately hepatocellular carcinoma (HCC). Emerging evidence has demonstrated the role in this transition of microRNAs (miRNAs), which regulate the expression of genes associated with lipid metabolism, inflammation, fibrosis, and cell proliferation. Specific miRNAs have been identified to exacerbate or mitigate fibrotic and carcinogenic processes in hepatic cells. The modulation of these miRNAs through synthetic mimics or inhibitors represents a promising therapeutic strategy. Preclinical models have demonstrated that miRNA-based therapies can attenuate liver inflammation, reduce fibrosis, and inhibit tumorigenesis, thus delaying or preventing the onset of HCC. However, challenges such as delivery mechanisms, off-target effects, and long-term safety remain to be addressed. This review, focusing on recently published preclinical and clinical studies, explores the pharmacological potential of miRNA-based interventions to prevent MASLD/MASH and progression toward HCC. [ABSTRACT FROM AUTHOR]

Summary: Microalgae are considered as attractive expression systems for the production of biologics. As photosynthetic unicellular organisms, they do not require costly and complex media for growing and are able to secrete proteins and perform protein glycosylation. Some biologics have been successfully produced in the green microalgae Chlamydomonas reinhardtii. However, post‐translational modifications like glycosylation of these Chlamydomonas‐made biologics have poorly been investigated so far. Therefore, in this study, we report on the first structural investigation of glycans linked to human erythropoietin (hEPO) expressed in a wild‐type C. reinhardtii strain and mutants impaired in key Golgi glycosyltransferases. The glycoproteomic analysis of recombinant hEPO (rhEPO) expressed in the wild‐type strain demonstrated that the three N‐glycosylation sites are 100% glycosylated with mature N‐glycans containing four to five mannose residues and carrying core xylose, core fucose and O‐methyl groups. Moreover, expression in C. reinhardtii insertional mutants defective in xylosyltransferases A and B and fucosyltransferase resulted in drastic decreases of core xylosylation and core fucosylation of glycans N‐linked to the rhEPOs, thus demonstrating that this strategy offers perspectives for humanizing the N‐glycosylation of the Chlamydomonas‐made biologics. [ABSTRACT FROM AUTHOR]

Recent years have witnessed significant advancements in the cryopreservation of various tissues and cells, yet several challenges persist. This review evaluates the current state of cryopreservation, focusing on contemporary methods, notable achievements, and ongoing difficulties. Techniques such as slow freezing and vitrification have enabled the successful preservation of diverse biological materials, including embryos and ovarian tissue, marking substantial progress in reproductive medicine and regenerative therapies. These achievements highlight improved post-thaw survival and functionality of cryopreserved samples. However, there are remaining challenges such as ice crystal formation, which can lead to cell damage, and the cryopreservation of larger, more complex tissues and organs. This review also explores the role of cryoprotectants and the importance of optimizing both cooling and warming rates to enhance preservation outcomes. Future research priorities include developing new cryoprotective agents, elucidating the mechanisms of cryoinjury, and refining protocols for preserving complex tissues and organs. This comprehensive overview underscores the transformative potential of cryopreservation in biomedicine, while emphasizing the necessity for ongoing innovation to address existing challenges. [ABSTRACT FROM AUTHOR]

Background: Lung cancer ranks as one of the most rapidly growing malignancies. Which is characterized by its poor prognosis and a low survival rate due to late diagnosis and limited efficacy of conventional treatments. In recent years nanotechnology has emerged as a promising frontier in the management of lung cancer, presenting novel strategies to enhance drug administration, improve therapeutic efficiency, and mitigate side effects. This research comprehensively evaluates the current state and research trends concerning the application of nanomaterials in lung cancer through bibliometric analysis. Materials and methods: We employed a systematic approach by retrieving studies from the Scopus database that focused on nanomaterials and lung cancer between 2003 and 2023. Subsequently, we carefully selected relevant articles based on predetermined inclusion criteria. The selected publications were then subjected to bibliometric and visual analysis using softwares such as VOSviewer and Biblioshiny. Results: A total of 3523 studies that meet inclusion criteria were selected for bibliometric analysis. We observed a progressive increase in the number of annual publications from 2003 to 2023, indicating the growing interest in this field. According to our analysis, China is the primary contributor to publication output among the countries. The "Ministry of Education of the People's Republic of China" was the most influential institution. Among the authors, "Dr. Jack A. Roth" and "Dr. Huang Leaf" had the highest number of publications and cited publications, respectively. The "International Journal of Nanomedicine" was found to be the most prolific journal in this field. Additionally, "Biomaterials" emerged as the most cited journal. Through keyword analysis, we identified five main research themes and future research directions; nono-immunotherapy and green synthesis are the hot topics in this research field. Conclusion: Our study summarized the key characteristics of publications in this field and identified the most influential countries, institutions, authors, journals, hot topics, and trends related to the application of nanomaterials in lung cancer. These findings contribute to the existing body of knowledge and serve as a foundation for future research endeavors in this area. More effective efforts are needed in this field to reduce the burden of lung cancer and help achieve the United Nation's Sustainable Development Goals. [ABSTRACT FROM AUTHOR]

Breast cancer (BC) is one of the frequent tumors that seriously endanger the physical and mental well-being in women with strong heterogeneity, and its pathogenesis involves multiple risk factors. Depending on the type of BC, hormonal therapy, targeted therapy, and immunotherapy are the current systemic treatment options along with conventional chemotherapy. Despite significant progress in understanding BC pathogenesis and therapeutic options, there is still a need to identify new therapeutic targets and develop more effective treatments. According to recent sequencing and profiling studies, non-coding (nc) RNAs genes are deregulated in human cancers via deletion, amplification, abnormal epigenetic, or transcriptional regulation, and similarly, the expression of many ncRNAs is altered in breast cancer cell lines and tissues. The ability of single ncRNAs to regulate the expression of multiple downstream gene targets and related pathways provides a theoretical basis for studying them for cancer therapeutic drug development and targeted delivery. Therefore, it is far-reaching to explore the role of ncRNAs in tumor development and their potential as therapeutic targets. Here, our review outlines the potential of two major ncRNAs, long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) as diagnostic and prognostic biomarkers as well as targets for new therapeutic strategies in breast cancer. [ABSTRACT FROM AUTHOR]

Using microRNAs (miRNAs) as potential circulating biomarkers in diagnosing and treating glioblastoma (GBM) has garnered a lot of scientific and clinical impetus in the past decade. As an aggressive primary brain tumor, GBM poses challenges in early detection and effective treatment with significant current diagnostic constraints and limited therapeutic strategies. MiRNA dysregulation is present in GBM. The intricate involvement of miRNAs in altering cell proliferation, invasion, and immune escape makes them prospective candidates for identifying and monitoring GBM diagnosis and response to treatment. These miRNAs could play a dual role, acting as both potential diagnostic markers and targets for therapy. By modulating the activity of various oncogenic and tumor-suppressive proteins, miRNAs create opportunities for precision medicine and targeted therapies in GBM. This review centers on the critical role and function of circulating miRNA biomarkers in GBM diagnosis and treatment. It highlights their significance in providing insights into disease progression, aiding in early diagnosis, and potential use as targets for novel therapeutic interventions. Ultimately, the study of miRNA would contribute to improving patient outcomes in the challenging landscape of GBM management. [ABSTRACT FROM AUTHOR]

Epithelial ovarian cancer (EOC) with its high death incidence rate is generally detected at advanced stages. During its progression, EOC often develops peritoneal metastasis aggravating the outcomes of EOC patients. Studies on non-coding RNAs (ncRNAs), such as microRNAs (miRNAs) and circular RNAs (circRNAs), have analyzed the impact of miRNAs and circRNAs, along with their interaction among each other, on cancer cells. MiRNAs can act as oncogenes or tumor suppressors modulating post-transcriptional gene expression. There is accumulating evidence that circRNAs apply their stable, covalently closed, continuous circular structures to competitively inhibit miRNA function, and so act as competing endogenous RNAs (ceRNAs). This interplay between both ncRNAs participates in the malignity of a variety of cancer types, including EOC. In the current review, I describe the characteristics of miRNAs and circRNAs, and discuss their interplay with each other in the development, progression, and drug resistance of EOC. Sponging of miRNAs by circRNAs may be used as a biomarker and therapeutic target in EOC. [ABSTRACT FROM AUTHOR]

Space exploration, with its enormous distances and extreme environments, is a challenge to technology, human habitation, sustainability, and supply chains. On the flip-side, however, it can provide a new vantage point on how to improve human life and planetary prosperity. This objective requires the development of economic and sustainable supply chains and a governance framework to guarantee fundamental human needs and well-being under the limitations of distant and inhospitable environments. This review describes learnings for human habitation in space from remote communities on Earth that have developed and survived over generations. These include a long history of human survival strategies on Tristan da Cunha, Pitcairn Islands, Nauru, and Easter Island. Their supply chain management solutions and their problems can guide the implementation of logistics systems for the efficient use of resources in space, to satisfy vital needs of human survival but also to ensure social and governance in space, e.g., build-up of thriving communities, mobility, and industrial activities. This review demonstrates that there are significant gaps in recent space supply chain studies with respect to the space environment, social and governance. Analysis of established practices and concepts from remote regions on Earth can readily respond to these deficiencies and thus supplement space exploration. This review recommends extending the assessment of supply-chain assets from the near future to long-term strategic. This implies going far beyond current space supply chain reports to include aspects of social responsibility and governance, such as sustainable health systems, product quality management, and local decision-making. [ABSTRACT FROM AUTHOR]

MRX34, a microRNA (miRNA)-based therapy for cancer, has recently entered clinical trials as the first clinical candidate in its class. It is a liposomal nanoparticle loaded with a synthetic mimic of the tumor suppressor miRNA miR-34a as the active pharmaceutical ingredient. To understand the pharmacokinetic properties of the drug and to rationalize an optimal dosing regimen in the clinic, a method is needed to quantitatively detect the miRNA mimic. Here, we report the development and qualification of a quantitative reverse transcription-polymerase chain reaction (qRT-PCR) assay in support of pharmacokinetic and toxicokinetic assessments in the nonhuman primate. Detection and quantification were performed on total ribonucleic acid (RNA) isolated from whole blood. The qualified range of the standard curve spans 6 orders of magnitude from 2.5 × 10(-7) to 2.5 × 10(-1) ng per reverse transcription (RT) reaction, corresponding to an estimated blood concentration from 6.2 × 10(-5) to 6.2 × 10(1) ng/mL. Our results demonstrate that endogenous as well as the exogenous miR-34a can be accurately and precisely quantified. The assay was used to establish the pharmacokinetic profile of MRX34, showing a favorable residence time and exposure of the miRNA mimic in whole blood from nonhuman primates.

The advancement in extraterrestrial exploration has highlighted the crucial need for studying how the human cardiovascular system adapts to space conditions. Human development occurs under the influence of gravity, shielded from space radiation by Earth's magnetic field, and within an environment characterized by 24-hour day-night cycles resulting from Earth's rotation, thus deviating from these conditions necessitates adaptive responses for survival. With upcoming manned lunar and Martian missions approaching rapidly, it is essential to understand the impact of various stressors induced by outer-space environments on cardiovascular health. This comprehensive review integrates insights from both actual space missions and simulated experiments on Earth, to analyze how microgravity, space radiation, and disrupted circadian affect cardiovascular well-being. Prolonged exposure to microgravity induces myocardial atrophy and endothelial dysfunction, which may be exacerbated by space radiation. Mitochondrial dysfunction and oxidative stress emerge as key underlying mechanisms along with disturbances in ion channel perturbations, cytoskeletal damage, and myofibril changes. Disruptions in circadian rhythms caused by factors such as microgravity, light exposure, and irregular work schedules, could further exacerbate cardiovascular issues. However, current research tends to predominantly focus on disruptions in the core clock gene, overlooking the multifactorial nature of circadian rhythm disturbances in space. Future space missions should prioritize targeted prevention strategies and early detection methods for identifying cardiovascular risks, to preserve astronaut health and ensure mission success. [ABSTRACT FROM AUTHOR]

Lung cancer is a prevalent malignancy and the leading cause of cancer-related deaths, posing a significant threat to human health. Despite advancements in treatment, the prognosis for lung cancer patients remains poor due to late diagnosis, cancer recurrence, and drug resistance. Epigenetic research, particularly in microRNAs, has introduced a new avenue for cancer prevention and treatment. MicroRNAs, including miR-137, play a vital role in tumor development by regulating various cellular processes. MiR-137 has garnered attention for its tumor-suppressive properties, with studies showing its potential in inhibiting cancer progression. In lung cancer, miR-137 is of particular interest, with numerous reports exploring its role and mechanisms. A comprehensive review is necessary to consolidate current evidence. This review highlights recent studies on miR-137 in lung cancer, covering cell proliferation, migration, apoptosis, drug resistance, and therapy, emphasizing its potential as a biomarker and therapeutic target for lung cancer treatment and prognosis. [ABSTRACT FROM AUTHOR]

Over the past three decades, significant progress has been made in elucidating the intricate connection between genetic predispositions and cardiovascular diseases (CVDs). Through extensive investigation, numerous genetic variants linked to various cardiovascular conditions have been discovered, shedding crucial light on the underlying biological mechanisms and pathways. These discoveries have not only revolutionized risk assessment for patients but have also paved the way for personalized treatment strategies, allowing healthcare providers to tailor interventions according to individual genetic profiles. Furthermore, genetic testing has facilitated cascade screening, enabling the early identification and intervention of potential cardiovascular issues among at-risk biological family members. This review aims to comprehensively summarize the current state of knowledge regarding inherited risk and novel insights from human genome and epigenome research, as well as therapeutic opportunities in CVDs with special emphasis on inherited cardiomyopathies and inherited arrhythmic syndromes. The newest translational trials for CVDs and pharmaceutical approaches are discussed, including gene therapy options for heart failure and cardiomyopathies. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) presents a significant global health burden, with alarming statistics revealing its rising incidence and high mortality rates. Despite advances in medical care, HCC treatment remains challenging due to late-stage diagnosis, limited effective therapeutic options, tumor heterogeneity, and drug resistance. MicroRNAs (miRNAs) have attracted substantial attention as key regulators of HCC pathogenesis. These small non-coding RNA molecules play pivotal roles in modulating gene expression, implicated in various cellular processes relevant to cancer development. Understanding the intricate network of miRNA-mediated molecular pathways in HCC is essential for unraveling the complex mechanisms underlying hepatocarcinogenesis and developing novel therapeutic approaches. This manuscript aims to provide a comprehensive review of recent experimental and clinical discoveries regarding the complex role of miRNAs in influencing the key hallmarks of HCC, as well as their promising clinical utility as potential therapeutic targets. [ABSTRACT FROM AUTHOR]

Transcription, RNA splicing, RNA translation, and post-translational protein modification are fundamental processes of gene expression. Epigenetic modifications, such as DNA methylation, RNA modifications, and protein modifications, play a crucial role in regulating gene expression. The methyltransferase-like protein (METTL) family, a constituent of the 7-β-strand (7BS) methyltransferase subfamily, is broadly distributed across the cell nucleus, cytoplasm, and mitochondria. Members of the METTL family, through their S-adenosyl methionine (SAM) binding domain, can transfer methyl groups to DNA, RNA, or proteins, thereby impacting processes such as DNA replication, transcription, and mRNA translation, to participate in the maintenance of normal function or promote disease development. This review primarily examines the involvement of the METTL family in normal cell differentiation, the maintenance of mitochondrial function, and its association with tumor formation, the nervous system, and cardiovascular diseases. Notably, the METTL family is intricately linked to cellular translation, particularly in its regulation of translation factors. Members represent important molecules in disease development processes and are associated with patient immunity and tolerance to radiotherapy and chemotherapy. Moreover, future research directions could include the development of drugs or antibodies targeting its structural domains, and utilizing nanomaterials to carry miRNA corresponding to METTL family mRNA. Additionally, the precise mechanisms underlying the interactions between the METTL family and cellular translation factors remain to be clarified. [ABSTRACT FROM AUTHOR]

Myelodysplastic syndromes (MDS) are a group of malignant clonal hematological disorders with heterogeneous clinical course and risk of transformation to acute myeloid leukemia. Genetic and epigenetic dysregulation, including alterations in microRNA (miRNA) expression, plays a pivotal role in MDS pathogenesis influencing disease development and progression. MiRNAs, known for their regulatory roles in gene expression, have emerged as promising biomarkers in various malignant diseases. This review aims to explore the diagnostic and prognostic roles of miRNAs in MDS. We discuss research efforts aimed at understanding the clinical utility of miRNAs in MDS management. MiRNA dysregulation is linked to specific chromosomal abnormalities in MDS, providing insights into themolecular landscape of the disease. Circulating miRNAs in plasma offer a less invasive avenue for diagnostic and prognostic assessment, with distinct miRNA profiles identified in MDS patients. Additionally, we discuss investigations concerning the role of miRNAs as markers for treatment response to hypomethylating and immunomodulating agents, which could lead to improved treatment decision-making and monitoring. Despite significant progress, further research in larger patient cohorts is needed to fully elucidate the role of miRNAs in MDS pathogenesis and refine personalized approaches to patient care. [ABSTRACT FROM AUTHOR]

Exosome‐derived microRNAs (miRNAs) are emerging as pivotal players in the pathophysiology of sepsis, representing a new frontier in both the diagnosis and treatment of this complex condition. Sepsis, a severe systemic response to infection, involves intricate immune and nonimmune mechanisms, where exosome‐mediated communication can significantly influence disease progression and outcomes. During the progress of sepsis, the miRNA profile of exosomes undergoes notable alterations, is reflecting, and may affect the progression of the disease. This review comprehensively explores the biology of exosome‐derived miRNAs, which originate from both immune cells (such as macrophages and dendritic cells) and nonimmune cells (such as endothelial and epithelial cells) and play a dynamic role in modulating pathways that affect the course of sepsis, including those related to inflammation, immune response, cell survival, and apoptosis. Taking into account these dynamic changes, we further discuss the potential of exosome‐derived miRNAs as biomarkers for the early detection and prognosis of sepsis and advantages over traditional biomarkers due to their stability and specificity. Furthermore, this review evaluates exosome‐based therapeutic miRNA delivery systems in sepsis, which may pave the way for targeted modulation of the septic response and personalized treatment options. [ABSTRACT FROM AUTHOR]

The study of immunometabolism, which examines how immune cells regulate their metabolism to maintain optimal performance, has become an important area of focus in cancer immunology. Recent advancements in this field have highlighted the intricate connection between metabolism and immune cell function, emphasizing the need for further research. MicroRNAs (miRNAs) have gained attention for their ability to post-transcriptionally regulate gene expression and impact various biological processes, including immune function and cancer progression. While the role of miRNAs in immunometabolism is still being explored, recent studies have demonstrated their significant influence on the metabolic activity of immune cells, such as macrophages, T cells, B cells, and dendritic cells, particularly in cancer contexts. Disrupted immune cell metabolism is a hallmark of cancer progression, and miRNAs have been linked to this process. Understanding the precise impact of miRNAs on immune cell metabolism in cancer is essential for the development of immunotherapeutic approaches. Targeting miRNAs may hold potential for creating groundbreaking cancer immunotherapies to reshape the tumor environment and improve treatment outcomes. In summary, the recognition of miRNAs as key regulators of immune cell metabolism across various cancers offers promising potential for refining cancer immunotherapies. Further investigation into how miRNAs affect immune cell metabolism could identify novel therapeutic targets and lead to the development of innovative cancer immunotherapies. [ABSTRACT FROM AUTHOR]

Introduction: Colorectal Cancer (CRC) is a significant health problem worldwide, with more than 70,000 new cancer cases recorded in India in 2020. A better understanding of CRC prognosis is needed. The substantial intratumoural heterogeneity among tumours of different stages has entailed the research for new biomarkers to more clearly identify tumour biology and behaviour. Micro Ribonucleic Acids (miRNAs) are non coding RNAs comprised of approximately 20-25 nucleotides and play an important role in epigenetic regulations. Studies have demonstrated that miRNAs play a critical role in tumourigenesis, metastasis, and tumour response to treatment. Comprehensive knowledge of miRNAs as potential markers of colon cancer diagnosis, prognosis, and predictive factors is crucial. Aim: To assess the miRNA signature (miR21, miR31, and miR34a) in colon cancer tumour samples and to evaluate the association of the miRNA signature with the clinicopathological profile and Pathological Tumour/Node/Metastasis (pTNM) stage of CRC patients. Materials and Methods: This cross-sectional and prospective study was conducted at the Departments of Pathology, Molecular Research and Diagnostics and Surgical Oncology of Sri Shankara Cancer Hospital, Bengaluru, Karnataka, India and was comprised of a total of 69 CRC patients who underwent surgery with a curative intent. The study was conducted over an 18-month period from January 2020 to June 2021. miRNA was extracted from Formalin-fixed Paraffin-embedded (FFPE) samples, and quantitative Polymerase Chain Reaction (qPCR) was done to get corresponding ΔCT (Threshold Cycles) values. The expression of miR21, miR31, and miR34a was evaluated, and their association with different clinicopathological parameters like age, sex, tumour stage, grade, Carcinoembryonic Antigen (CEA) levels, Perineural Invasion (PNI), and Lymphovascular Invasion (LVI) status was studied. The expression of the mentioned miRNAs was assigned low and high values on the basis of median values. Spearman's correlation was done to check for any significant associations. Results: All three miRNAs (miR21, miR31, miR34a) were found to have lower values in the >60 years age group compared to the <60 years age group. Higher values of miRNA were found in male patients than in females, with a p-value of 0.022 for miR21. However, miRNA expression (miR21, miR31, miR34a) did not show any statistically significant correlation with tumour location (p-values 0.543, 0.255, 0.255), lymph node status (p-values 0.676, 0.153, 0.930), TNM stage (p-values 0.273, 0.509, 0.898), LVI (p-values 0.233, 0.233, 0.733), PNI (p-values 0.686, 0.263, 0.756), and serum CEA level (p-values 0.543, 0.255, 0.255). Conclusion: The present study showed the possible tumoursuppressive role of miR34a in CRC. Although miR21 acts as an oncogenic miRNA in many cancers, in CRC, its expression differs between males and females, with most tumours in males exhibiting high expression. [ABSTRACT FROM AUTHOR]

A prolific scientific literature attributes pro- or anti-oncogenic properties to many human microRNAs ("miRNAs"). While many of these studies are based on unpersuasive analyses, one candidate suppressor tumour miRNA, miR-34a, appeared convincing enough to be administered to human patients in a clinical trial-with disappointing outcomes. Here, we review possible reasons for that failure, and their implications for other miRNAs., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

The number and function of myeloid cells in the lungs are critical determinants of health and disease. To examine whether these cells can be modulated in vivo by a colony-stimulating factor (CSF), recombinant human granulocyte macrophage-CSF (GM-CSF) was given to cynomolgus monkeys by either continuous intravenous infusion (7,200 U/kg/day) for 2 wk or by aerosol exposure to 10(7) U on 1 or 2 consecutive days. At intervals after the initiation of GM-CSF administration, animals underwent bronchoalveolar lavage (BAL) and had peripheral blood sampled to characterize changes in lung and circulating phagocytic cells. Compared with animals exposed to bovine serum albumin, there was an increase in the total number of BAL cells retrieved. This increase was greatest in animals receiving aerosolized GM-CSF, and it was the result of more macrophages and neutrophils. Both lung macrophages and blood neutrophils from animals exposed to aerosolized GM-CSF exhibited an augmented respiratory burst in response to phorbol myristate acetate. Lung macrophages from GM-CSF-exposed animals exhibited increased capacity to bind and/or ingest opsonized and unopsonized Staphylococcus aureus. Despite functional activation of lung phagocytic cells, biochemical analyses of BAL fluid for markers of lung injury revealed an increase in only some parameters in the GM-CSF group. Intravenous administration of GM-CSF had the expected effect on augmenting the number of myeloid cells in the bloodstream. Aerosolized GM-CSF produced a transient effect on circulating myeloid cell number between 3 and 5 days after exposure.(ABSTRACT TRUNCATED AT 250 WORDS)

While significant progress has been made in understanding and applying gene silencing mechanisms and the treatment of human diseases, there have been still several obstacles in therapeutic use. For the first time, ONPATTRO, as the first small interfering RNA (siRNA) based drug was invented in 2018 for treatment of hTTR with polyneuropathy. Additionally, four other siRNA based drugs naming Givosiran, Inclisiran, Lumasiran, and Vutrisiran have been approved by the US Food and Drug Administration and the European Medicines Agency for clinical use by hitherto. In this review, we have discussed the key and promising advances in the development of siRNA-based drugs in preclinical and clinical stages, the impact of these molecules in bacterial and viral infection diseases, delivery system issues, the impact of administration methods, limitations of siRNA application and how to overcome them and a glimpse into future developments. [ABSTRACT FROM AUTHOR]

Osteosarcoma (OS) is the most prevalent and fatal type of bone tumor. It is characterized by great heterogeneity of genomic aberrations, mutated genes, and cell types contribution, making therapy and patients management particularly challenging. A unifying picture of molecular mechanisms underlying the disease could help to transform those challenges into opportunities. This review deeply explores the occurrence in OS of large-scale RNA regulatory networks, denominated "competing endogenous RNA network" (ceRNET), wherein different RNA biotypes, such as long non-coding RNAs, circular RNAs and mRNAs can functionally interact each other by competitively binding to shared microRNAs. Here, we discuss how the unbalancing of any network component can derail the entire circuit, driving OS onset and progression by impacting on cell proliferation, migration, invasion, tumor growth and metastasis, and even chemotherapeutic resistance, as distilled from many studies. Intriguingly, the aberrant expression of the networks components in OS cells can be triggered also by the surroundings, through cytokines and vesicles, with their bioactive cargo of proteins and non-coding RNAs, highlighting the relevance of tumor microenvironment. A comprehensive picture of RNA regulatory networks underlying OS could pave the way for the development of innovative RNA-targeted and RNA-based therapies and new diagnostic tools, also in the perspective of precision oncology. [ABSTRACT FROM AUTHOR]