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American Society of Clinical Oncology... Jun 2024The management of renal cell carcinoma (RCC) has advanced significantly in the past two decades. Many promising functional imaging modalities such as radiolabeled tracer... (Review)
Review
The management of renal cell carcinoma (RCC) has advanced significantly in the past two decades. Many promising functional imaging modalities such as radiolabeled tracer targeting carbonic anhydrase IX and prostate-specific membrane antigen are under development to detect primary kidney tumors, stage systemic disease, and assess treatment response in RCC. Immune checkpoint inhibitors targeting PD-1 and cytotoxic T-cell lymphocyte-4 have changed the treatment paradigm in advanced RCC. Trials investigating novel mechanisms such as LAG-3 immune checkpoint inhibition, chimeric antigen receptor T-cell therapies, and T-cell engagers targeting RCC-associated antigens are currently ongoing. With the rapidly changing treatment landscape of RCC, the treatment sequence strategies will continue to evolve. Familiarity with the toxicities associated with the therapeutic agents and how to manage them are essential to achieve optimal patient outcomes. This review summarizes the recent developments of functional imaging and immunotherapy strategies in RCC, and the evidence supports treatment sequencing.
Topics: Humans; Carcinoma, Renal Cell; Immunotherapy; Kidney Neoplasms; Immune Checkpoint Inhibitors
PubMed: 38875505
DOI: 10.1200/EDBK_438658 -
PloS One 2024Ewing sarcoma is the second most common bone cancer in children, and while patients who present with metastatic disease at the time of diagnosis have a dismal prognosis....
Ewing sarcoma is the second most common bone cancer in children, and while patients who present with metastatic disease at the time of diagnosis have a dismal prognosis. Ewing sarcoma tumors are driven by the fusion gene EWS/Fli1, and while these tumors are genetically homogenous, the transcriptional heterogeneity can lead to a variety of cellular processes including metastasis. In this study, we demonstrate that in Ewing sarcoma cells, the canonical Wnt/β-Catenin signaling pathway is heterogeneously activated in vitro and in vivo, correlating with hypoxia and EWS/Fli1 activity. Ewing sarcoma cells predominantly express β-Catenin on the cell membrane bound to CDH11, which can respond to exogenous Wnt ligands leading to the immediate activation of Wnt/β-Catenin signaling within a tumor. Knockdown of CDH11 leads to delayed and decreased response to exogenous Wnt ligand stimulation, and ultimately decreased metastatic propensity. Our findings strongly indicate that CDH11 is a key component of regulating Wnt//β-Catenin signaling heterogeneity within Ewing sarcoma tumors, and is a promising molecular target to alter Wnt//β-Catenin signaling in Ewing sarcoma patients.
Topics: Sarcoma, Ewing; Humans; Cadherins; Wnt Signaling Pathway; Cell Line, Tumor; beta Catenin; Animals; Bone Neoplasms; Mice; Oncogene Proteins, Fusion; Proto-Oncogene Protein c-fli-1; RNA-Binding Protein EWS
PubMed: 38875295
DOI: 10.1371/journal.pone.0305490 -
The Journal of Clinical Investigation Jun 2024GNAO1 mutated in pediatric encephalopathies encodes the major neuronal G-protein Gαo. Of >80 pathogenic mutations, most are single amino acid substitutions spreading...
GNAO1 mutated in pediatric encephalopathies encodes the major neuronal G-protein Gαo. Of >80 pathogenic mutations, most are single amino acid substitutions spreading across Gαo sequence. We perform extensive characterization of Gαo mutants showing abnormal GTP uptake and hydrolysis, and deficiencies to bind Gβγ and RGS19. Plasma membrane localization of Gαo is decreased for a subset of mutations that leads to epilepsy; dominant interactions with GPCRs also emerge for the more severe mutants. Pathogenic mutants massively gain interaction with Ric8A and, surprisingly, Ric8B proteins, delocalizing them from cytoplasm to Golgi. Of these two mandatory Gα-subunit chaperones, Ric8A is normally responsible for the Gαi/o, Gαq, and Gα12/13 subfamilies, and Ric8B solely for Gαs/olf. Ric8A/B mediate the disease dominance when engaging in neomorphic interactions with pathogenic Gαo through disbalancing the neuronal G protein signaling networks. As the strength of Gαo-Ric8B interactions correlates with disease severity, our study further identifies an efficient biomarker and predictor for clinical manifestations in GNAO1 encephalopathies. Our work discovers the neomorphic molecular mechanism of mutations underlying pediatric encephalopathies and offers insights to other maladies caused by G protein misfunctioning and further genetic diseases.
PubMed: 38874642
DOI: 10.1172/JCI172057 -
MBio Jun 2024Mitogen-activated protein kinase (MAPK) pathways are fundamental to the regulation of biological processes in eukaryotic organisms. The basidiomycete , known for causing...
Mitogen-activated protein kinase (MAPK) pathways are fundamental to the regulation of biological processes in eukaryotic organisms. The basidiomycete , known for causing fungal meningitis worldwide, possesses five MAPKs. Among these, Cpk1, Hog1, and Mpk1 have established roles in sexual reproduction, stress responses, and cell wall integrity. However, the roles of Cpk2 and Mpk2 are less understood. Our study elucidates the functional interplay between the Cpk1/Cpk2 and Mpk1/Mpk2 MAPK pathways in . We discovered that overexpression compensates for Δ mating deficiencies via the Mat2 transcription factor, revealing functional redundancy between Cpk1 and Cpk2. We also found that Mpk2 is phosphorylated in response to cell wall stress, a process regulated by the MAPK kinase (MAP2K) Mkk2 and MAP2K kinases (MAP3Ks) Ssk2 and Ste11. Overexpression of partially restores cell wall integrity in Δ by influencing key cell wall components, such as chitin and the polysaccharide capsule. Contrarily, overexpression cannot restore thermotolerance and cell membrane integrity in Δ. These results suggest that Mpk1 and Mpk2 have redundant and opposing roles in the cellular response to cell wall and membrane stresses. Most notably, the dual deletion of and restores wild-type mating efficiency in Δ mutants via upregulation of the mating-regulating transcription factors and , suggesting that the Mpk1 and Mpk2 cooperate to negatively regulate the pheromone-responsive Cpk1 MAPK pathway. Our research collectively underscores a sophisticated regulatory network of cryptococcal MAPK signaling pathways that intricately govern sexual reproduction and cell wall integrity, thereby controlling fungal development and pathogenicity.IMPORTANCEIn the realm of fungal biology, our study on offers pivotal insights into the roles of specific proteins called mitogen-activated protein kinases (MAPKs). Here, we discovered the cryptic functions of Cpk2 and Mpk2, two MAPKs previously overshadowed by their dominant counterparts Cpk1 and Mpk1, respectively. Our findings reveal that these "underdog" proteins are not just backup players; they play crucial roles in vital processes like mating and cell wall maintenance in . Their ability to step in and compensate when their dominant counterparts are absent showcases the adaptability of . This newfound understanding not only enriches our knowledge of fungal MAPK mechanisms but also underscores the intricate balance and interplay of proteins in ensuring the organism's survival and adaptability.
PubMed: 38874410
DOI: 10.1128/mbio.01156-24 -
The ISME Journal Jun 2024Although enteric bacteria normally reside within the animal intestine, the ability to persist extraintestinally is an essential part of their overall lifestyle, and it...
Although enteric bacteria normally reside within the animal intestine, the ability to persist extraintestinally is an essential part of their overall lifestyle, and it might contribute to transmission between hosts. Despite this potential importance, few genetic determinants of extraintestinal growth and survival have been identified, even for the best-studied model, Escherichia coli. In this work, we thus used a genome-wide library of barcoded transposon insertions to systematically identify functional clusters of genes that are crucial for E. coli fitness in lake water. Our results revealed that inactivation of pathways involved in maintaining outer membrane integrity, nucleotide biosynthesis, and chemotaxis negatively affected E. coli growth or survival in this extraintestinal environment. In contrast, inactivation of another group of genes apparently benefited E. coli growth or persistence in filtered lake water, resulting in higher abundance of these mutants. This group included rpoS, which encodes the general stress response sigma factor, and genes encoding several other global transcriptional regulators and RNA chaperones, as well as several poorly annotated genes. Based on this co-enrichment, we identified these gene products as novel positive regulators of RpoS activity. We further observed that, despite their enhanced growth, E. coli mutants with inactive RpoS had reduced viability in lake water, and they were not enriched in the presence of the autochthonous microbiota. This highlights the duality of the general stress response pathway for E. coli growth outside the host.
PubMed: 38874171
DOI: 10.1093/ismejo/wrae096 -
Frontiers in Chemistry 2024Mitochondria are the energy factories of cells and are important targets for the development of novel tumour treatment strategies owing to their involvement in processes... (Review)
Review
Mitochondria are the energy factories of cells and are important targets for the development of novel tumour treatment strategies owing to their involvement in processes such as apoptosis, oxidative stress, and metabolic programming. Thiosemicarbazone metal complexes target mitochondria and reduce mitochondrial membrane potential. The breakdown of mitochondrial membrane potential is a key event in the early stage of apoptosis, which releases cytochrome C and other pro-apoptotic factors, activates the intracellular apoptotic enzyme cascade, and eventually causes irreversible apoptosis of tumour cells. Thiosemicarbazone metal complexes targeting the mitochondria have recently emerged as potential antitumour agents; therefore, this review describes the structural diversity of thiosemicarbazone metal [Fe(III), Cu(II), Ni(II), Zn(II), Ga(III), Pb(II), Au(III), and Ir(III)] complexes and explores their anti-tumour mechanisms that target mitochondrial pathways.
PubMed: 38873408
DOI: 10.3389/fchem.2024.1424022 -
Bioactive Materials Oct 2024Previous studies have confirmed that intervertebral disc degeneration (IDD) is closely associated with inflammation-induced reactive oxygen species (ROS) and resultant...
Previous studies have confirmed that intervertebral disc degeneration (IDD) is closely associated with inflammation-induced reactive oxygen species (ROS) and resultant cell mitochondrial membrane potential (MMP) decline. Clearance of ROS in an inflammatory environment is essential for breaking the vicious cycle of MMP decline. Additionally, re-energizing the mitochondria damaged in the inflammatory milieu to restore their function, is equally important. Herein, we proposed an interesting concept of mitochondrion-engine equipped with coolant, which enables first to "cool-down" the inflammatory environment, next to restore the MMP, finally to allow cells to regain normal energy metabolism through materials design. As such, we developed a multi-functional composite composed of a reactive oxygen species (ROS)-responsive sodium alginate/gelatin hydrogel infused into a rigid 3D-printed thermoplastic polyurethane (TPU) scaffold. The TPU scaffold was coated with conductive polypyrrole (PPy) to electrophoretically deposit l-arginine, which could upregulate the Mammalian target of rapamycin () pathway, thus increasing MMP and energy metabolism to stimulate extracellular matrix synthesis for IVD repair. While the ROS-responsive hydrogel acting as the "mito-engine coolant" could scavenge the excessive ROS to create a favorable environment for IVD cells recovery. Demonstrated by and evaluations, the mito-engine system markedly promoted the proliferation and collagen synthesis of nucleus pulposus cells while enhancing the mitochondrial respiration and MMP under oxidative stress. Radiological and histological assessments revealed the efficacy of this system in IVD repair. This unique bioinspired design integrated biomaterial science with mitochondrial biology, presents a promising paradigm for IDD treatment.
PubMed: 38873262
DOI: 10.1016/j.bioactmat.2024.05.044 -
Frontiers in Microbiology 2024Porcine epidemic diarrhea virus (PEDV) is a single-stranded RNA virus with a capsid membrane that causes acute infectious gastrointestinal disease characterized by... (Review)
Review
Porcine epidemic diarrhea virus (PEDV) is a single-stranded RNA virus with a capsid membrane that causes acute infectious gastrointestinal disease characterized by vomiting, diarrhea, and dehydration in swine. Piglets are more susceptible to PEDV than adults, with an infection rate reaching 90% and a fatality rate as high as 100%. Moreover, PEDV has a rapid transmission rate and broad transmission range. Consequently, PEDV has caused considerable economic losses and negatively impacted the sustainability of the pig industry. The surface spike (S) glycoprotein is the largest structural protein in PEDV virions and is closely associated with host cell fusion and virus invasion. As such, the S protein is an important target for vaccine development. In this article, we review the genetic variation, immunity, apoptosis-induction function, virulence, vaccine potential, and other aspects of the PEDV S protein. This review provides a theoretical foundation for preventing and controlling PEDV infection and serves as a valuable resource for further research and development of PEDV vaccines.
PubMed: 38873162
DOI: 10.3389/fmicb.2024.1396894 -
Frontiers in Microbiology 2024() infection and the rapid spread of multi-drug resistant (MDR) bacteria pose a serious threat to global healthcare. Polymyxin E (colistin), a group of cationic...
() infection and the rapid spread of multi-drug resistant (MDR) bacteria pose a serious threat to global healthcare. Polymyxin E (colistin), a group of cationic antimicrobial polypeptides, is currently one of the last resort treatment options against carbapenem-resistant Gram-negative pathogens. The effectiveness of colistin has been compromised due to its intensive use. This study found that fingolimod (FLD), a natural product derivative, exhibited a significant synergistic bactericidal effect on when combined with colistin, both and . The checkerboard method was employed to assess the synergistic effect of FLD with colistin. FLD enhanced the susceptibility of bacteria to colistin and lowered effectively minimum inhibitory concentrations (MIC) when compared to colistin MIC, and the fractional inhibitory concentrations (FIC) value was less than 0.3. The time-kill curve demonstrated that the combination treatment of FLD and colistin had significant bactericidal efficacy. The concurrent administration of colistin and FLD resulted in heightening membrane permeability, compromising cell integrity, diminishing membrane fluidity, and perturbing membrane homeostasis. They also induced alterations in membrane potential, levels of reactive oxygen species, and adenosine triphosphate synthesis, ultimately culminating in bacterial death. Moreover, the combination of FLD with colistin significantly influenced fatty acid metabolism. In the mouse infection model, the survival rate of mice injected with was significantly improved to 67% and pathological damage was significantly relieved with combination treatment of FLD and colistin when compared with colistin treatment. This study highlights the potential of FLD in combining with colistin for treating infections caused by MDR isolates of .
PubMed: 38873155
DOI: 10.3389/fmicb.2024.1396663 -
Chemical Science Jun 2024Many biological processes generally require long-term visualization tools for time-scale dynamic changes of the plasma membrane, but there is still a lack of design...
Many biological processes generally require long-term visualization tools for time-scale dynamic changes of the plasma membrane, but there is still a lack of design rules for such imaging tools based on small-molecule fluorescent probes. Herein, we revealed the key regulatory roles of charge number and species of fluorescent dyes in the anchoring ability of the plasma membrane and found that the introduction of multi-charged units and appropriate charge species is often required for fluorescent dyes with strong plasma membrane anchoring ability by systematically investigating the structure-function relationship of cyanostyrylpyridium (CSP) dyes with different charge numbers and species and their imaging performance for the plasma membrane. The CSP-DBO dye constructed exhibits strong plasma membrane anchoring ability in staining the plasma membrane of cells, in addition to many other advantages such as excellent biocompatibility and general universality of cell types. Such a fluorescent anchor has been successfully used to monitor chemically induced plasma membrane damage and dynamically track various cellular biological events such as cell fusion and cytokinesis over a long period of time by continuously monitoring the dynamic morphological changes of the plasma membrane, providing a valuable precise visualization tool to study the physiological response to chemical stimuli and reveal the structural morphological changes and functions of the plasma membrane during these important biological events from a dynamic perspective. Furthermore, CSP-DBO exhibits excellent biocompatibility and imaging capability such as labelling the plasma membrane and monitoring the metabolic process of lipofuscin as an aging indicator.
PubMed: 38873067
DOI: 10.1039/d4sc01423e