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Frontiers in Oncology 2024Mitomycin-C (MMC) chemotherapy is a well-established anti-cancer treatment for non-muscle-invasive bladder cancer (NMIBC). However, despite comprehensive biological...
Mitomycin-C (MMC) chemotherapy is a well-established anti-cancer treatment for non-muscle-invasive bladder cancer (NMIBC). However, despite comprehensive biological research, the complete mechanism of action and an ideal regimen of MMC have not been elucidated. In this study, we present a theoretical investigation of NMIBC growth and its treatment by continuous administration of MMC chemotherapy. Using temporal ordinary differential equations (ODEs) to describe cell populations and drug molecules, we formulated the first mathematical model of tumor-immune interactions in the treatment of MMC for NMIBC, based on biological sources. Several hypothetical scenarios for NMIBC under the assumption that tumor size correlates with cell count are presented, depicting the evolution of tumors classified as small, medium, and large. These scenarios align qualitatively with clinical observations of lower recurrence rates for tumor size ≤ 30[mm] with MMC treatment, demonstrating that cure appears up to a theoretical [mm] tumor size threshold, given specific parameters within a feasible biological range. The unique use of mole units allows to introduce a new method for theoretical pre-treatment assessments by determining MMC drug doses required for a cure. In this way, our approach provides initial steps toward personalized MMC chemotherapy for NMIBC patients, offering the possibility of new insights and potentially holding the key to unlocking some of its mysteries.
PubMed: 38884094
DOI: 10.3389/fonc.2024.1352065 -
MedRxiv : the Preprint Server For... Jun 2024CD4-mimetics (CD4mcs) are small molecule compounds that mimic the interaction of the CD4 receptor with HIV-1 envelope glycoproteins (Env). Env from primary viruses...
UNLABELLED
CD4-mimetics (CD4mcs) are small molecule compounds that mimic the interaction of the CD4 receptor with HIV-1 envelope glycoproteins (Env). Env from primary viruses normally samples a "closed" conformation which occludes epitopes recognized by CD4-induced (CD4i) non-neutralizing antibodies (nnAbs). CD4mcs induce conformational changes on Env resulting in the exposure of these otherwise inaccessible epitopes. Here we evaluated the capacity of plasma from a cohort of 50 people living with HIV to recognize HIV-1-infected cells and eliminate them by antibody-dependent cellular cytotoxicity (ADCC) in the presence of a potent indoline CD4mc. We observed a marked heterogeneity among plasma samples. By measuring the levels of different families of CD4i Abs, we found that the levels of anti-cluster A, anti-coreceptor binding site and anti-gp41 cluster I antibodies are responsible for plasma-mediated ADCC in presence of CD4mc.
IMPORTANCE
There are several reasons that make it difficult to target the HIV reservoir. One of them, is the capacity of infected cells to prevent the recognition of HIV-1 envelope glycoproteins (Env) by commonly-elicited antibodies in people living with HIV. Small CD4-mimetic compounds expose otherwise occluded Env epitopes, thus enabling their recognition by non-neutralizing antibodies. A better understanding of the contribution of these antibodies to eliminate infected cells in presence of CD4mc could lead to the development of therapeutic cure strategies.
PubMed: 38883797
DOI: 10.1101/2024.06.02.24308281 -
Research Square Jun 2024Synovial Sarcoma (SS) is driven by the SS18::SSX fusion oncoprotein and is ultimately refractory to therapeutic approaches. SS18::SSX alters ATP-dependent chromatin...
Synovial Sarcoma (SS) is driven by the SS18::SSX fusion oncoprotein and is ultimately refractory to therapeutic approaches. SS18::SSX alters ATP-dependent chromatin remodeling BAF (mammalian SWI/SNF) complexes, leading to the degradation of canonical (cBAF) complex and amplified presence of an SS18::SSX-containing non-canonical BAF (ncBAF or GBAF) that drives an SS-specific transcription program and tumorigenesis. We demonstrate that SS18::SSX activates the SUMOylation program and SSs are sensitive to the small molecule SAE1/2 inhibitor, TAK-981. Mechanistically, TAK-981 de-SUMOylates the cBAF subunit SMARCE1, stabilizing and restoring cBAF on chromatin, shifting away from SS18::SSX-ncBAF-driven transcription, associated with DNA damage and cell death and resulting in tumor inhibition across both human and mouse SS tumor models. TAK-981 synergized with cytotoxic chemotherapy through increased DNA damage, leading to tumor regression. Targeting the SUMOylation pathway in SS restores cBAF complexes and blocks the SS18::SSX-ncBAF transcriptome, identifying a therapeutic vulnerability in SS, positioning the in-clinic TAK-981 to treat SS.
PubMed: 38883782
DOI: 10.21203/rs.3.rs-4362092/v1 -
Research Square Jun 2024Mutations in RNA splicing factor genes including SF3B1, U2AF1, SRSF2, and ZRSR2 have been reported to contribute to development of myeloid neoplasms including...
Mutations in RNA splicing factor genes including SF3B1, U2AF1, SRSF2, and ZRSR2 have been reported to contribute to development of myeloid neoplasms including myelodysplastic syndrome (MDS) and secondary acute myeloid leukemia (sAML). Chemical tools targeting cells carrying these mutant genes remain limited and underdeveloped. Among the four proteins, mutant U2AF1 (U2AF1 ) acquires an altered 3' splice site selection preference and co-operates with the wild-type U2AF1 (U2AF1 ) to change various gene isoform patterns to support MDS cells survival and proliferation. U2AF1 mutations in MDS cells are always heterozygous and the cell viability is reduced when exposed to additional insult affecting U2AF1 function. To investigate if the pharmacological inhibition of U2AF1wt function can provoke drug-induced vulnerability of cells harboring U2AF1mut, we conducted a fragment-based library screening campaign to discover compounds targeting the U2AF homology domain (UHM) in U2AF1 that is required for the formation of the U2AF1/U2AF2 complex to define the 3' splice site. The most promising hit (SF1-8) selectively inhibited growth of leukemia cell lines overexpressingU2AF1 and human primary MDS cells carrying U2AF1 . RNA-seq analysis of K562-U2AF1 following treatment with SF1-8 further revealed alteration of isoform patterns for a set of proteins that impair or rescue pathways associated with endocytosis, intracellular vesicle transport, and secretion. Our data suggested that further optimization of SF1-8 is warranted to obtain chemical probes that can be used to evaluate the therapeutic concept of inducing lethality to U2AF1 cells by inhibiting the U2AF1 protein.
PubMed: 38883705
DOI: 10.21203/rs.3.rs-4477663/v1 -
Frontiers in Bioengineering and... 2024Virus-like particles (VLPs) are a promising class of biopharmaceuticals for vaccines and targeted delivery. Starting from clarified lysate, VLPs are typically captured...
Virus-like particles (VLPs) are a promising class of biopharmaceuticals for vaccines and targeted delivery. Starting from clarified lysate, VLPs are typically captured by selective precipitation. While VLP precipitation is induced by step-wise or continuous precipitant addition, current monitoring approaches do not support the direct product quantification, and analytical methods usually require various, time-consuming processing and sample preparation steps. Here, the application of Raman spectroscopy combined with chemometric methods may allow the simultaneous quantification of the precipitated VLPs and precipitant owing to its demonstrated advantages in analyzing crude, complex mixtures. In this study, we present a Raman spectroscopy-based Process Analytical Technology (PAT) tool developed on batch and fed-batch precipitation experiments of Hepatitis B core Antigen VLPs. We conducted small-scale precipitation experiments providing a diversified data set with varying precipitation dynamics and backgrounds induced by initial dilution or spiking of clarified -derived lysates. For the Raman spectroscopy data, various preprocessing operations were systematically combined allowing the identification of a preprocessing pipeline, which proved to effectively eliminate initial lysate composition variations as well as most interferences attributed to precipitates and the precipitant present in solution. The calibrated partial least squares models seamlessly predicted the precipitant concentration with of 0.98 and 0.97 in batch and fed-batch experiments, respectively, and captured the observed precipitation trends with of 0.74 and 0.64. Although the resolution of fine differences between experiments was limited due to the observed non-linear relationship between spectral data and the VLP concentration, this study provides a foundation for employing Raman spectroscopy as a PAT sensor for monitoring VLP precipitation processes with the potential to extend its applicability to other phase-behavior dependent processes or molecules.
PubMed: 38882637
DOI: 10.3389/fbioe.2024.1399938 -
Frontiers in Psychiatry 2024Emerging evidence links cellular senescence to the pathogenesis of major depressive disorder (MDD), a life-threatening and debilitating mental illness. However, the...
BACKGROUND
Emerging evidence links cellular senescence to the pathogenesis of major depressive disorder (MDD), a life-threatening and debilitating mental illness. However, the roles of cellular senescence-related genes in MDD are largely unknown and were investigated in this study using a comprehensive analysis.
METHODS
Peripheral blood microarray sequencing data were downloaded from Gene Expression Omnibus (GEO) database and retrieved cellular senescence-related genes from CellAge database. A weighted gene co-expression network analysis was used to screen MDD-associated genes. Protein-protein interactions (PPI) were predicted based on STRING data, and four topological algorithms were used to identify hub genes from the PPI network. Immune infiltration was evaluated using CIBERSORT, followed by a correlation analysis between hub genes and immune cells.
RESULTS
A total of 84 cell senescence-related genes were differentially expressed in patients with MDD compared to healthy control participants. Among the 84 genes, 20 were identified to be associated with the MDD disease phenotype, and these genes were mainly involved in hormone-related signaling pathways (such as estrogen, steroid hormone, and corticosteroid) and immune and inflammatory pathways. Three genes, namely, JUN, CTSD, and CALR, which were downregulated in MDD, were identified as the hub genes. The expression of hub genes significantly moderate correlated with multiple immune cells, such as Tregs, NK cells, and CD4+ T cells, and the abundance of these immune cells markedly differed in MDD samples. Multiple microRNAs, transcription factors, and small-molecule drugs targeting hub genes were predicted to explore their molecular regulatory mechanisms and potential therapeutic value in MDD.
CONCLUSION
JUN, CTSD, and CALR were identified as potential diagnostic markers of MDD and may be involved in the immunoinflammatory mechanism of MDD.
PubMed: 38881549
DOI: 10.3389/fpsyt.2024.1372386 -
Journal of Microbiology and... Jun 2024Fungi employ diverse mechanisms for iron uptake to ensure proliferation and survival in ironlimited environments. Siderophores are secondary metabolite small molecules... (Review)
Review
Fungi employ diverse mechanisms for iron uptake to ensure proliferation and survival in ironlimited environments. Siderophores are secondary metabolite small molecules with a high affinity specifically for ferric iron; these molecules play an essential role in iron acquisition in fungi and significantly influence fungal physiology and virulence. Fungal siderophores, which are primarily hydroxamate types, are synthesized via non-ribosomal peptide synthetases (NRPS) or NRPSindependent pathways. Following synthesis, siderophores are excreted, chelate iron, and are transported into the cell by specific cell membrane transporters. In several human pathogenic fungi, siderophores are pivotal for virulence, as inhibition of their synthesis or transport significantly reduces disease in murine models of infection. This review briefly highlights siderophore biosynthesis and transport mechanisms in fungal pathogens as well the model fungi and Understanding siderophore biosynthesis and transport in pathogenic fungi provides valuable insights into fungal biology and illuminates potential therapeutic targets for combating fungal infections.
PubMed: 38881181
DOI: 10.4014/jmb.2405.05020 -
Zhongguo Fei Ai Za Zhi = Chinese... May 2024Lung cancer is the most common malignant disease and the leading cause of cancer death in China. Non-small cell lung cancer (NSCLC) accounts for over 80% of all lung... (Review)
Review
Lung cancer is the most common malignant disease and the leading cause of cancer death in China. Non-small cell lung cancer (NSCLC) accounts for over 80% of all lung cancers, and the probability of NSCLC gene mutations is high, with a wide variety of types. With the development of next-generation sequencing (NGS) detection technology, more and more patients with rare fusion gene mutations are detected. Neuregulin 1 (NRG1) gene is a rare oncogenic driver that can lead to activation of human epidermal growth factor receptor 3 (Her3/ErbB3) mediated pathway, resulting in tumor formation. In this article, we reported a case of mixed NSCLC with CRISPLD2-NRG1 fusion detected by RNA-based NGS, who responsed to Afatinib well after 1 month of treatment, and magnetic resonance imaging (MRI) showed shrinkage of intracranial lesions. Meanwhile, we also compiled previously reported NSCLC patients with NRG1 rare gene fusion mutation, in order to provide effective references for clinical diagnosis and treatment. .
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Neuregulin-1; Afatinib; Oncogene Proteins, Fusion; Middle Aged; Male; Cell Adhesion Molecules; Female
PubMed: 38880928
DOI: 10.3779/j.issn.1009-3419.2024.102.19 -
Cost Effectiveness and Resource... Jun 2024Alzheimer's disease (AD), breast cancer (BC) and prostate cancer (PC) continue to be high in the research and innovation agenda of the European Commission (EC). This is...
Alzheimer's disease (AD), breast cancer (BC) and prostate cancer (PC) continue to be high in the research and innovation agenda of the European Commission (EC). This is due to their exceptionally large burden to the national health systems, the profound economic effects of opportunity costs attributable to decreased working ability, premature mortality and the ever-increasing demand for both hospital and home-based medical care. Over the last two decades, the EC has been steadily increasing both the number of proposals being funded and the amounts of financial resources being allocated to these fields of research. This trend has continued throughout four consecutive science funding cycles, namely framework programme (FP)5, FP6, FP7 and Horizon 2020 (H2020). We performed a retrospective assessment of the outputs and outcomes of EC funding in AD, BC and PC research over the 1999-2019 period by means of selected indicators. These indicators were assessed for their ability to screen the past, present and future for an array of causal relationships and long-term trends in clinical, epidemiological and public health sphere, while considering also the broader socioeconomic impact of funded research on the society at large. This analysis shows that public-private partnerships with large industry and university-based consortia have led to some of the most impactful proposals being funded over the analysed time period. New pharmaceuticals, small molecules and monoclonal antibodies alike, along with screening and prevention, have been the most prominent sources of innovation in BC and PC, extending patients' survival and enhancing their quality of life. Unlike oncology, dementia drug development has been way less successful, with only minor improvements related to the quality of supportive medical care for symptoms and more sensitive diagnostics, without any ground-breaking disease-modifying treatment(s). Significant progresses in imaging diagnostics and nanotechnology have been largely driven by the participation of medical device industry multinational companies. Clinical trials funded by the EC were conducted, leading to the development of brand-new drug molecules featuring novel mechanisms of action. Some prominent cases of breakthrough discoveries serve as evidence for the European capability to generate cutting-edge technological innovation in biomedicine. Less productive areas of research may be reconsidered as priorities when shaping the new agenda for forthcoming science funding programmes.
PubMed: 38880873
DOI: 10.1186/s12962-024-00540-5 -
BMC Neurology Jun 2024Hypoxia can cause a variety of diseases, including ischemic stroke and neurodegenerative diseases. Within a certain range of partial pressure of oxygen, cells can...
Hypoxia can cause a variety of diseases, including ischemic stroke and neurodegenerative diseases. Within a certain range of partial pressure of oxygen, cells can respond to changes in oxygen. Changes in oxygen concentration beyond a threshold will cause damage or even necrosis of tissues and organs, especially for the central nervous system. Therefore, it is very important to find appropriate measures to alleviate damage. MiRNAs can participate in the regulation of hypoxic responses in various types of cells. MiRNAs are involved in regulating hypoxic responses in many types of tissues by activating the hypoxia-inducible factor (HIF) to affect angiogenesis, glycolysis and other biological processes. By analyzing differentially expressed miRNAs in hypoxia and hypoxia-related studies, as well as the HT22 neuronal cell line under hypoxic stress, we found that the expression of miR-18a was changed in these models. MiR-18a could regulate glucose metabolism in HT22 cells under hypoxic stress by directly regulating the 3'UTR of the Hif1a gene. As a small molecule, miRNAs are easy to be designed into small nucleic acid drugs, so this study can provide a theoretical basis for the research and treatment of nervous system diseases caused by hypoxia.
Topics: MicroRNAs; Glucose; Hypoxia-Inducible Factor 1, alpha Subunit; Hippocampus; Neurons; Animals; Mice; Cell Hypoxia; Cell Line; Humans
PubMed: 38879468
DOI: 10.1186/s12883-024-03717-w