Preeclampsia (PE) contributes to pregnancy-related morbidity and mortality, with enhanced inflammation. Healthy placenta stem cells (P-MSCs) can be licensed into immune suppressor cells to mitigate inflammation. Since PE is associated with inflammation, the question is why the associated P-MSCs cannot suppress the response. PE P-MSCs have been shown to be dysfunctional with respect to decreased anti-inflammatory response, cell cycle dysregulation, and reduced production of immune suppressive cytokines. Aspirin (ASA) treatment partly reversed these dysfunctions via epigenetic reprogramming. We tested the hypothesis that extracellular vesicles (EVs) from healthy P-MSC could reset PE P-MSCs to a healthy phenotype, including cell cycle dysregulation and anti-inflammatory licensing. EVs from healthy MSCs were collected and the number of particles quantified. The isolated EVs were added to PE P-MSCs. Control cultures treated the PE P-MSCs with 1 mM ASA. The treated cells were assessed for the epigene regulator TDG and cell cycle linked CDK4, p21, and p53 by western blot, or assessed as third-party suppression in a one-way mixed lymphocyte reaction (MLR). EV- and ASA-treated PE P-MSC suppressed MLR, similar to healthy P-MSCs. However, an evaluation of p21, CDK4, p53, and TDG suggested that EVs impart a more stable restoration of PE P-MSCs when exposed to healthy EVs. This study provides insights into the method by which healthy P-MSCs can function to restore PE P-MSCs, and in vivo microenvironmental restoration.
This opinion article discusses the findings of a published article, which reported on the mechanism by which neuronal substance P (SP) drives metastasis through an extracellular RNA–TLR7 axis [1]. The role of SP in cancer is not a novel finding. Rather, SP’s effect on cancer is linked to a long-held view on the neural–hematopoietic axis. Since the article omitted several seminal findings, we organized this review/commentary that discusses the landscape of SP in breast cancer. We also include our collective thoughts on the cited article that mostly support the past literature. Our article is intended to enhance the field of the neural-substance P-cancer axis and applaud the authors for their exciting findings. We believe that their findings further underscore the need to target breast cancer with an SP receptor antagonist. In this regard, we propose repurposing of aprepitant to treat breast cancer.
Mesenchymal stem cells (MSCs) are multipotent stromal cells that can differentiate into cells of the three germ layers. MSCs exhibit immune plasticity and this property is guided by the inflammatory tissue niche. Importantly, MSCs can be licensed as immune suppressor cells within an inflammatory niche. Since MSCs are approved by the food and drug administration for particular inflammation, it is important to determine how these cells maintain multipotency, in particular, the fate of these cells in vivo when they become located within a varied tissue niche. More importantly, the molecular mechanisms by which MSCs maintain multipotency will improve clinical applications. The focus of this study is particularly important since MSCs are available off the shelf, indicating allogeneic differences between the recipient and donor. We studied the transcription factor NFκB since it is a central regulator of inflammation. NFκB also links intrinsic stem cell signaling and extrinsic inflammatory cues. We used in silico analyses and determined that NFκB could regulate the major stem cell genes such as Octamer 4A (Oct4A). We confirmed a canonical pathway using an NFκB array that dissected the intracellular pathway. Additionally, we used specific small molecules to inhibit NFκB subunits. Using published RNA-Seq data, we showed a potential role for the purinergic receptors with a key role for ADORA2B. Similar to the licensing of MSCs by inflammatory mediators, ADORA2B appeared to be regulated by growth factors, including those linked to inflammation. In total, NFκB regulates MSC multipotency in a cell-autonomous manner, explaining the licensing properties within an inflammatory microenvironment. We also showed that the purinergic receptors could be involved in intrinsic and extrinsic regulation of MSC multipotency.
Oct4 is among the key genes involved in pluripotency. Oct4, through alternative splicing, produces at least three different transcripts, Oct4a, Oct4b, and Oct4b1. The Oct4a transcript has been focused on due to its role in pluripotency and multipotency of stem cells. There are several Oct4 pseudogenes with at least seven identified in the human genome. Some of these Oct4 pseudogenes have been found in various cancers. The Oct4 pseudogenes share high homology to the Oct4a transcript. There is limited information on the biologic role of Oct4 pseudogenes. More importantly, it is unclear how these pseudogenes affect the biology of the full-length transcript. Thus, it is important to understand these pseudogenes since their biology could lead to a better understanding of differentiation, cancer, and dedifferentiation to form cancer stem cells. This brief report used in silico analyses to analyze Oct4 and its pseudogenes. The implication for the findings on stem cells and cancer, as well as other related genes, are discussed.
Extracellular vesicles (exosomes) can mediate intercellular communication. In cancer patients, exosomes are central to intercellular communication between cancer cells and non-malignant cells within the tissue niche, and at distant regions. This type of communication influences the biology of the cancer and treatment response. This study tested the hypothesis that carbon beads, 150–500 μm in size with pore size about 27 nm, can capture exosomes from the plasma of cancer patients, and from a glioblastoma cell line (T98G). The challenge to addressing the hypothesis is the relatively larger size of exosomes, 50–120 nm, to be captured within the carbon pore. This study tested plasma from a patient with ovarian cancer and two breast cancer patients, HER2+ and triple negative for hormone receptor (TNBC), and released exosomes from T98G cells. This study showed exosomes from ovarian plasma binding to a specific synthetic carbon, C529. Similar binding did not occur with plasma from age-matched healthy controls. GBM exosomes also bound to C529 but the repertoire of carbon was broader. TNBC exosomes showed low affinity for the identified carbon. However, exosomes from HER2+ breast cancer were able to bind to the carbon beads. In total, this study showed binding of exosomes from cancer plasma to C529 carbon. The results of these findings are discussed in the context of potential treatment, and they provide future direction for studies to examine carbon beads as adjuvant or neoadjuvant treatment for cancer.
The International Space Station (ISS) is a collaborative platform for advanced research in microgravity, significantly contributing to cancer studies, drug development, and tissue engineering. Since its assembly in 1998, the ISS has become an invaluable environment for experiments not possible on Earth. A key focus is organoid development – miniature, 3D human organ models grown in space, offering insights into disease mechanisms, drug responses, and regenerative medicine. Microgravity promotes scaffold-free tissue formation, advancing neurodegenerative disease research and therapeutic discovery. Cancer research on the ISS has expanded since the 2010s, using microgravity to grow 3D tumor models that mimic human tumors more accurately than Earth-based systems. These studies have improved our understanding of cancer cell behavior, chemotherapy resistance, and immune responses, driving new drug development. NASA’s collaboration with initiatives like the Cancer Moonshot accelerates cancer research in space. Emerging biomarker studies in space are enhancing early cancer detection and environmental monitoring. Additionally, ISS research on radiation-induced DNA damage has led to improved diagnostic tools, such as microsatellite instability (MSI) tests, which aid in cancer detection and treatment planning. Overall, the ISS continues to push boundaries in biomedical research, offering novel insights that are transforming cancer biology, regenerative medicine, and precision health, with far-reaching implications for human health on Earth and beyond.
There is continued interest in applying adult human mesenchymal stem cells (MSCs) in tissue regeneration, as well as mitigating overt inflammation such as graft versus host disease. MSCs are derived from different sources such as bone marrow, bone chips, dental pulp, adipose tissues, and placenta. MSCs appear to exert a memory for their tissue of origin. Interestingly, despite positive outcomes of MSCs in vivo, their survival in host tissues appears to be short-lived. To date, based on research and clinical literature, there is a need to understand how MSCs are maintained in a multipotent state. We discuss the role for the inflammatory milieu in which soluble and insoluble such as exosomes can determine the immune response of MSCs – suppressor versus enhancer. This article discusses a central role for the transcription factor NFκB in maintaining multipotency, and discusses how the inflammatory milieu influences the differentiation of MSCs. Lessons are drawn from the literature on MSCs in cancer to further describe the role of NFκB in maintaining the stem cell state. The findings outlined in this article could be important to future translational studies.
The oral cavity is a site of hematopoietic activity, and metastatic hematological and solid tumors. This study focused on acute myeloid leukemia (AML) due to extensive documentation of its presentation in the gingiva. Despite these reports, it is unclear how AML and other leukemia cells survive in the oral tissue. We investigated intercellular communication between leukemia cells and dental pulp stem cells (DPSCs). DPSCs enhanced the proliferation and adhesion of AML cells (HL-60) and to a lesser extent, myelomoncytic leukemia cells (U937). The erythroleukemia K562 cells showed a delayed trend to proliferate. The communication between DPSCs and HL-60 cells was partly due to gap junctional intercellular communication (GJIC), as indicated by dye transfer. We also noted evidence of tunnelling nanotubules (TNT). Dye transfer was noted in non-adherent cells, suggesting other method of transfer, perhaps by extracellular vesicles. Using SORE-6 that can stratify the HL-60 subset, dye transfer occurred mostly in the subset lowest in the hierarchy. These latter findings were novel since they might provide insights into the behavior of non-leukemia stem cells and their interaction with cells in the oral cavity. In summary, this study began to dissect the interaction between HL-60 AML cells and DPSCs, providing insights into the survival of AML and perhaps other leukemia cells in the oral cavity.
Coxsackie B typically affects one organ system at a time – heart, liver or lungs. There is sparce literature on multiorgan failure induced by the Coxsackie B virus. Here we describe a case of Coxsackie B in a young female with type 1 diabetes mellitus. At admission to the hospital, the patient was presented with complaints of fatigue, lethargy, nausea, vomiting and hypoglycemia. Additionally, the patient was found to have myopericarditis, transaminitis, and acute renal failure requiring temporary hemodialysis. While myopericarditis is frequently associated with Coxsackie B, both hepatic and/or renal failure are uncommon presentations. Treatment is largely supportive with NSAIDs as the most effective treatment for myopericarditis.
Electroporation is an essential biophysical process that involves the use of pulsed electric fields to temporarily increase the permeability of cell membranes. A comprehensive overview of the main clinical and biomedical applications of cellular electroporation is provided here with a particular focus on cancer therapy, genetics, and drug delivery. The review concentrates on the characterization of membrane stresses caused by electroporation and their impact on cell membrane structure and dynamics. It analyses the relationship between applied electric fields, cell geometry, and membrane composition with the aim of developing mathematical models to simulate cell geometries and the electroporation process. Furthermore, it identifies both the beneficial effects and potential complications of the electroporation treatment, as well as the various mathematical models that have been developed to simulate the effects of such treatments. The use of sophisticated simulation algorithms enables an in-depth investigation of the intricate relationship between electrical parameters and cellular responses, facilitating a comprehensive assessment of the efficacy and safety of the electroporation procedures.
Herein, we report the synthesis of a new stable zero/one-dimensional composite heterostructure “MXeneCeria” by integrating titanium carbide MXene (Ti3C2Tx) nanosheets-derived quantum dots with nano-octahedral particles of ceria (CeO2). This unique assimilation resulted in the formation of an auto-fluorescent aqueous colloidal material, which is detectable in fluorescent colors across various wavelengths, ranging from blue to green and red. The unique physicochemical properties of MXeneCeria make it a very promising nanocomposite and it may open a gateway to its potential applications in the biomedical field including tracking, immunoengineering, cell therapy, and targeted drug delivery.
Despite early diagnosis and improved treatments, breast cancer remains a challenging disease. A strategic advantage for breast cancer recurrence is the ability of breast cancer cells to become quiescent and survive for decades in a dormant state within the endosteal region of the bone marrow. Breast cancer dormancy is triggered by exosome vesicles secreted by mesenchymal stem cells residing in the bone marrow. By mechanisms yet to be determined, dormant breast cancer cells are awakened leading to resurgence and metastasis. Experimental evidence supports the notion that dormant breast cancer cells are cancer stem cells recognized as tumor initiating and propagating cells with chemoresistant and metastatic properties. These cells represent less than 2% of the total tumor mass, which impose a significant barrier for their therapeutic targeting. This review focuses on cellular and molecular properties of breast cancer dormancy including tumor microenvironment, epigenetic regulation, cell signaling and metabolic reprogramming.
For over 20 years, scientists aboard the International Space Station (the “ISS”) have been expanding the boundaries of scientific knowledge. Leveraging microgravity and other extreme conditions unique to space, these scientists have made significant discoveries in cellular behavior, tissue engineering, gene expression, organism growth patterns, and regenerative medicine. This article aims to introduce the pharmaceutical and biotechnology communities to the exciting possibilities and challenges of conducting research and development (“R&D”) in space. The scientific advantages of space-based drug R&D are compelling. Experiments conducted aboard the ISS National Lab, along with ground-based studies, reveal unique features that cannot be replicated under normal gravity conditions. For instance, space-based drug research has shown that microgravity conditions enable more efficient 3D cell cultures, improved protein crystal growth, and open up new possibilities for 3D printing of biomaterials, cells, tissues, and organs.
Chrono-nutrition, a concept emerging from the integration of chronobiology and nutrition sciences, investigates the timing of food intake in alignment with the body’s circadian rhythms. This interplay between dietary patterns and biological rhythms has garnered significant attention in recent years due to its potential implications for health and disease. In this comprehensive review, we explore the key findings from studies in the last decade on chrono-nutrition, focusing on its role in cardiovascular health, diabetes management, glucose metabolism, and the influence of sex, socioeconomic factors, and cultural diversity. The intricate dance between the molecular circadian clock and the gut microbiome is a fascinating area of study in modern biology. Both systems are integral to the regulation of metabolic processes, responding to dietary inputs and environmental cues to optimize the host’s adaptability and survival. This review delves into the dynamic interplay between circadian rhythms and the gut microbiome, exploring their mutual influence and the implications for human health.
This review article addresses an area of the literature with unanswered questions; although relevant to future treatment of leukemias. The literature describes bone marrow stromal microenvironment as support of leukemias. A key stromal support is mesenchymal stem cells (MSCs), which are similar to those identified in oral tissues, including the dental pulp (DPSC). Hematopoiesis has been reported in oral tissues, although the described activity seems to be distinct from extramedullary hematopoiesis at other sites when there is bone marrow dysfunction such as myelofibrosis. Another parallel between the bone marrow and oral tissues is the survival of leukemia cells. This review describes cases in which the dentist diagnoses leukemia, in particular acute myeloid leukemia (AML). The literature showed AML and other hematological malignancies in gingiva, leaving the question of the source of leukemia. We propose that this question is relevant considering the similar stromal support in bone marrow and oral tissues. It is difficult to determine if current treatments can target leukemia in oral tissues. This article consists of information to argue for continued research in this field.
Thirty years ago, the most prominent cardiovascular scientists gathered in a medieval town near Rome to scrutinize the actual possibility of regenerating the myocardium. They agreed to the vision, but the knowledge and technology available were not mature to allow the development of clinically suitable protocols for regenerating the post-ischemic cardiac muscle. Subsequent intensive efforts of thousand scientists and exorbitant investments worldwide have generated many progresses without unraveling the complexity of using healthy cells or fabricating stripes of engineered tissue to be implanted in injured hearts. However, even if the final goal appears not yet at hand, the lesson learned brings us much closer to efficient protocols for clinical use.
Space medicine is a branch of aerospace medicine, which is a crucial field, albeit with minimal research. Research at the International Space Station and other endeavors has provided insights into how loss of gravity could affect the physiological functions of humans. Organs such as the heart could begin to deteriorate with lack of resistance from the planet. The musculoskeletal system, which is the anatomical backbone, may struggle to support the individual’s structure. The cardiovascular system will be inefficient with respect to circulation, leading to other organ dysfunction. Radiation in space, also known as cosmic radiation, is caused by many different celestial bodies such as stars, sun, supernovae, and black holes. The Earth’s magnetic field is a crucial component to protect humans from harmful radiation. However, once humans venture beyond the protective confines, the body becomes exposed to dangerous elements that pose a significant threat to safety. Living in microgravity also has detrimental effects on organisms’ brains. These include but are not limited to sustained effects on circadian rhythm, emotional dysregulation, and cognitive dysfunction. This article discusses the threat of premature aging during long- and short-term times in space due to high risks associated with space travel. Improvement of clinical intervention is hindered by a lack of research and development, which is needed to fundamentally address these risks.
Glioblastoma multiform (GBM), a grade IV glioma, is the most common and aggressive cancer in the central nervous system. Current treatment for GBM includes surgical resection, radiation, and the frontline DNA alkylating drug, temozolomide (TMZ). The current median survival for GBM patients is about 14.5 months with 5% patients surviving up to 5 years. We propose that discerning distinct subsets within heterogeneous GBM will provide avenues for research to improve new therapies. We used different methods to isolate GBM cell subsets. These include stable transfectants of GBM cell lines with a lentiviral system in which green fluorescence protein (GFP) is regulated with tandem repeats of Oct4a and Sox2 response elements. Parallel studies with a plasmid using the full-length regulatory region of Oct4a indicated reduced efficiency in separating cell subsets, relative to SORE6-GFP lentivirus. Stem cell-linked gene expressions and function studies such as ALDH1, tumorsphere and in vivo passaging of GFP hi subsets confirmed the presence of cancer stem cells (CSCs). We also studied a more efficient method that could be relevant for primary GBM cells. We selected tumorspheres by plating heterogeneous GBM cells and then serially passaged the spheres. Studies for stem cell genes indicated that this method could be used for primary GBM cells. Overall, this study provided insights into methods to isolate GBM subsets, including primary GBM cells. The advantages of the methods are discussed.
We previously reported on high expression of define PDCD2 in human malignancies. Knockdown of PDCD2 reduced the proliferation of leukemia and lung carcinoma cells. However, the mechanism by which PDCD2 reduces tumor proliferation remains unclear. This study tested the hypothesis that lowered PDCD2 would delay the proliferation of A549 lung carcinoma cells. Entry of A549 cells into S-phase was significantly (p-value 0.05) delayed when PDCD2 was knockdown. This correlated with a significant downregulation of cyclin D1, and AKT phosphorylation. Inhibition of the PI3K/AKT signaling pathway by Ly294002 decreased levels of PDCD2. These findings are consistent with a role for PDCD2 to mediate the entry of A549 cells into the cell cycle. Resting A549 cells showed PDCD2 localizing in the nucleus and plasma membrane and became diffuse with cell division, suggesting that PDCD2 is mitogen-dependent and may be involved in the proper timing of cell cycle. These findings may represent a promising venue to develop PDCD2 in clinical applications.
This is a commentary article using data reported by the United States Drug Approval (FDA) system for clinical trials. The text surmised reasons for this delay. The data show continued delay to impact drugs reaching patients. Instead of increasing drug approval, the statistics showed a trend of increased numbers of drug on hold. The reason for these delays need to be evaluated, and perhaps to apply new technologies to evaluate the data.
