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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 -
Cancer Control : Journal of the Moffitt... 2024The present study aimed to evaluate the frequencies of , and mutations and their possible associations with clinicopathological features in 249 Moroccan patients with...
OBJECTIVES
The present study aimed to evaluate the frequencies of , and mutations and their possible associations with clinicopathological features in 249 Moroccan patients with colorectal cancer (CRC).
METHODS
A retrospective investigation of a cohort of formalin-fixed paraffin-embedded tissues of 249 patients with CRC was screened for // mutations using Idylla™ technology and pyrosequencing.
RESULTS
, and mutations were revealed in 46.6% (116/249), 5.6% (14/249), and 2.4% (6/249) of patients. exon 2 mutations were identified in 87.9% of patients (102/116). G12D and G12 C were the most frequent, at 32.8% and 12.93%, respectively. Among the patients with exon 2 wild-type (wt), 27.6% (32/116) harbored additional mutations. Concurrent mutations were identified in 9.5% (11/116); including six in codon 146 (A146P/T/V), three in codon 61 (Q61H/L/R), one in codon 12 (G12 A and Q61H), and one in codon 13 (G13D and Q61 L). Among the exon 2 wt patients, 64.3% (9/14) harbored additional mutations. Concurrent mutations were identified in 28.6% (4/14) of -mutant patients. Since 3.2% wt were identified with mutations, concomitant and mutations were identified in 2.4% (6/249) of patients. mutations were higher in the >50-year-old age-group ( = .031), and the tumor location was revealed to be significantly associated with mutations ( = .028) predominantly in left colon (27.5%) and colon (42.2%) locations. mutations were most prevalent in the left colon (42.8%) and in well-differentiated tumors (64.2%).
CONCLUSION
Detection of mutations, particularly the G12 C subtype, may be significant for patients with CRC and has possible therapeutic implications. However, rare concomitant mutations in CRC patients suggest that each individual may present distinct therapeutic responses. testing alongside the identification of other affected genes in the same patient will make the treatments even more personalized by contributing more accurately to the clinical decision process. Overall, early diagnosis using novel molecular techniques may improve the management of CRC by providing the most efficient therapies for Moroccan patients.
Topics: Humans; Proto-Oncogene Proteins B-raf; Colorectal Neoplasms; Male; Female; Proto-Oncogene Proteins p21(ras); Membrane Proteins; Middle Aged; GTP Phosphohydrolases; Morocco; Mutation; Retrospective Studies; Aged; Adult; Aged, 80 and over; DNA Mutational Analysis
PubMed: 38875469
DOI: 10.1177/10732748241262179 -
Medicine Jun 2024This study aims to analyze the effective components of Polygonum capitatum (PC) inhibiting Escherichia coli based on network pharmacology methods and predict its... (Review)
Review
This study aims to analyze the effective components of Polygonum capitatum (PC) inhibiting Escherichia coli based on network pharmacology methods and predict its molecular mechanism of action. PC compounds and targets were collected from the TCMSP database, Swiss Target Prediction, and the literature. E coli targets were searched using the GeneCards database. The targets of E coli and the targets of the active ingredients of PC were taken as intersections to obtain the intersecting targets. The resulting overlapping targets were uploaded to the STRING database to construct the protein interaction network diagram of E coli target inhibition. The key targets for the inhibitory effect of PC on E coli were obtained. Gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were performed by uploading key targets into the DAVID database. The results showed that there were 50 targets for PC to inhibit E coli. Among them, there are 5 core targets, mainly including AKT1, TNF, EGFR, JUN, and ESR1. A total of 196 gene ontology functional analysis results and 126 Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis results were obtained. These include cellular response to cadmium-ion, cellular response to reactive oxygen species, pathways in cancer, prostate cancer, and PI3K-Akt signaling pathway. Molecular docking results indicate that Lutedin, Hirsutin, Flazin, and Ellagic acid in PC have high affinity for the target genes AKT1, TNF, MAPK3 and EGFR. PC exerts its inhibitory effect on E coli through multi-targets and multi-pathways, which provides a new basis for the new use of PC as an old medicine.
Topics: Polygonum; Molecular Docking Simulation; Escherichia coli; Network Pharmacology; Humans; Protein Interaction Maps; Drugs, Chinese Herbal
PubMed: 38875382
DOI: 10.1097/MD.0000000000038536 -
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 -
European Journal of Sport Science Jun 2024A sedentary lifestyle and Olympic participation are contrary risk factors for global mortality and incidence of cancer and cardiovascular disease. Extracellular vesicle...
Next-generation sequencing reveals that miR-16-5p, miR-19a-3p, miR-451a, and miR-25-3p cargo in plasma extracellular vesicles differentiates sedentary young males from athletes.
A sedentary lifestyle and Olympic participation are contrary risk factors for global mortality and incidence of cancer and cardiovascular disease. Extracellular vesicle miRNAs have been described to respond to exercise. No molecular characterization of young male sedentary people versus athletes is available; so, our aim was to identify the extracellular vesicle miRNA profile of chronically trained young endurance and resistance male athletes compared to their sedentary counterparts. A descriptive case-control design was used with 16 sedentary young men, 16 Olympic male endurance athletes, and 16 Olympic male resistance athletes. Next-generation sequencing and RT-qPCR and external and internal validation were performed in order to analyze extracellular vesicle miRNA profiles. Endurance and resistance athletes had significant lower levels of miR-16-5p, miR-19a-3p, and miR-451a compared to sedentary people. Taking all together, exercise-trained miRNA profile in extracellular vesicles provides a differential signature of athletes irrespective of the type of exercise compared to sedentary people. Besides, miR-25-3p levels were specifically lower in endurance athletes which defines its role as a specific responder in this type of athletes. In silico analysis of this profile suggests a role in adaptive energy metabolism in this context that needs to be experimentally validated. Therefore, this study provides for the first time basal levels of circulating miRNA in extracellular vesicles emerge as relevant players in intertissue communication in response to chronic exercise exposure in young elite male athletes.
Topics: Humans; Male; MicroRNAs; Extracellular Vesicles; Sedentary Behavior; Athletes; Case-Control Studies; Young Adult; High-Throughput Nucleotide Sequencing; Physical Endurance; Adolescent
PubMed: 38874986
DOI: 10.1002/ejsc.12087 -
European Journal of Sport Science Jun 2024This study examined the impact of continuous blood flow restriction (BFR) during repeated-sprint exercise (RSE) on acute performance, peripheral, systemic physiological,... (Randomized Controlled Trial)
Randomized Controlled Trial
This study examined the impact of continuous blood flow restriction (BFR) during repeated-sprint exercise (RSE) on acute performance, peripheral, systemic physiological, and perceptual responses. In a randomized crossover design, 26 adult male semi-professional and amateur team-sport players completed two RSE sessions (3 sets of 5 × 5-s sprints with 25 s of passive recovery and 3 min of rest) with continuous BFR (45% arterial occlusion; excluding during between-set rest periods) or without (non-BFR). Mean and peak power output were significantly lower (p < 0.001) during BFR compared to non-BFR (d = 0.85 and 0.77, respectively). Minimum tissue saturation index during the sprints and rest periods was significantly reduced (p < 0.001) for BFR (d = 1.26 and 1.21, respectively). Electromyography root mean square was significantly decreased (p < 0.01) for biceps femoris and lateral gastrocnemius muscles during BFR (d = 0.35 and 0.79, respectively), but remained unchanged for the vastus lateralis muscle in both conditions. Oxygen consumption and minute ventilation were significantly reduced (both p < 0.01) for BFR (d = 1.46 and 0.43, respectively). Perceived limb discomfort was significantly higher (p < 0.001) for BFR (d = 0.78). No differences (p > 0.05) in blood lactate concentration or rating of perceived exertion were observed between conditions. Blood flow-restricted RSE reduced performance and likely increased the physiological and perceptual stimulus for the periphery with greater reliance on anaerobic glycolysis, despite comparable or decreased systemic demands.
Topics: Humans; Male; Cross-Over Studies; Oxygen Consumption; Young Adult; Adult; Muscle, Skeletal; Regional Blood Flow; Electromyography; Running; Athletic Performance; Perception
PubMed: 38874946
DOI: 10.1002/ejsc.12106 -
Aging Jun 2024Prostate cancer is one of the serious health problems of older male, about 13% of male was affected by prostate cancer. Prostate cancer is highly heterogeneity disease...
Prostate cancer is one of the serious health problems of older male, about 13% of male was affected by prostate cancer. Prostate cancer is highly heterogeneity disease with complex molecular and genetic alterations. So, targeting the gene candidates in prostate cancer in single-cell level can be a promising approach for treating prostate cancer. In the present study, we analyzed the single cell sequencing data obtained from 2 previous reports to determine the differential gene expression of prostate cancer in single-cell level. By using the network pharmacology analysis, we identified the therapeutic targets of formononetin in immune cells and tissue cells of prostate cancer. We then applied molecular docking to determine the possible direct binding of formononetin to its target proteins. Our result identified a cluster of differential gene expression in prostate cancer which can serve as novel biomarkers such as immunoglobulin kappa C for prostate cancer prognosis. The result of network pharmacology delineated the roles of formononetin's targets such CD74 and THBS1 in immune cells' function of prostate cancer. Also, formononetin targeted insulin receptor and zinc-alpha-2-glycoprotein which play important roles in metabolisms of tissue cells of prostate cancer. The result of molecular docking suggested the direct binding of formononetin to its target proteins including INSR, TNF, and CXCR4. Finally, we validated our findings by using formononetin-treated human prostate cancer cell DU145. For the first time, our result suggested the use of formononetin for treating prostate cancer through targeting different cell types in a single-cell level.
PubMed: 38874510
DOI: 10.18632/aging.205935 -
Aging Jun 2024Exploring the molecular mechanisms of PD-1/PDL-1 blockade for non-small cell lung cancer (NSCLC) would facilitate understanding for tumor microenvironment (TME) and...
Exploring the molecular mechanisms of PD-1/PDL-1 blockade for non-small cell lung cancer (NSCLC) would facilitate understanding for tumor microenvironment (TME) and development of individualized medicine. To date, biomarkers of response to PD-1 blockade therapy were still limited. In this study, we hypothesize that cell type in the tumor microenvironment can influence the effect of PD-1 blockade immunotherapy through specific genes. Therefore, we re-analyze the single-cell RNA sequencing data and validation in tissue from lung adenocarcinoma patients. Dynamic changes of cellular subpopulation were observed after anti-PD-1 immunotherapy among TMEs between primary/metastasis or good/poor response patients. Non-exhausted CD8 T cells and dysregulated genes were observed in responsing patients from PD-1 blockade therapy. Among all changed genes, JUN, involved in PD-1 blockade immunotherapy pathway, and could be considered as a PD-1 responsing biomarker.
PubMed: 38874497
DOI: 10.18632/aging.205932 -
Microbiology Spectrum Jun 2024The human polyomavirus, JCPyV, establishes a lifelong persistent infection in the peripheral organs of a majority of the human population worldwide. Patients who are...
JCPyV infection of primary choroid plexus epithelial cells reduces expression of critical junctional proteins and increases expression of barrier disrupting inflammatory cytokines.
UNLABELLED
The human polyomavirus, JCPyV, establishes a lifelong persistent infection in the peripheral organs of a majority of the human population worldwide. Patients who are immunocompromised due to underlying infections, cancer, or to immunomodulatory treatments for autoimmune disease are at risk for developing progressive multifocal leukoencephalopathy (PML) when the virus invades the CNS and infects macroglial cells in the brain parenchyma. It is not yet known how the virus enters the CNS to cause disease. The blood-choroid plexus barrier is a potential site of virus invasion as the cells that make up this barrier are known to be infected with virus both and . To understand the effects of virus infection on these cells we challenged primary human choroid plexus epithelial cells with JCPyV and profiled changes in host gene expression. We found that viral infection induced the expression of proinflammatory chemokines and downregulated junctional proteins essential for maintaining blood-CSF and blood-brain barrier function. These data contribute to our understanding of how JCPyV infection of the choroid plexus can modulate the host cell response to neuroinvasive pathogens.
IMPORTANCE
The human polyomavirus, JCPyV, causes a rapidly progressing demyelinating disease in the CNS of patients whose immune systems are compromised. JCPyV infection has been demonstrated in the choroid plexus both and and this highly vascularized organ may be important in viral invasion of brain parenchyma. Our data show that infection of primary choroid plexus epithelial cells results in increased expression of pro-inflammatory chemokines and downregulation of critical junctional proteins that maintain the blood-CSF barrier. These data have direct implications for mechanisms used by JCPyV to invade the CNS and cause neurological disease.
PubMed: 38874395
DOI: 10.1128/spectrum.00628-24 -
Human & Experimental Toxicology 2024Stereotactic body radiation therapy (SBRT) is a targeted form of radiotherapy used to treat early-stage cancers. Despite its effectiveness, the impact of SBRT on...
BACKGROUND
Stereotactic body radiation therapy (SBRT) is a targeted form of radiotherapy used to treat early-stage cancers. Despite its effectiveness, the impact of SBRT on myeloid-derived suppressor cells (MDSCs) is not well understood. In this study, we examined how SBRT affects the differentiation and survival of MDSCs, as well as delved into the molecular mechanisms involved.
METHODS AND RESULTS
SBRT was utilized on bone marrow (BM)-derived MDSCs to investigate its impact on the differentiation and survival of MDSCs using flow cytometry. An animal model of lung cancer was created to assess the anti-cancer properties of SBRT and the role of miR-21 expression in MDSCs. The interplay of miR-21 and Sorbin and SH3 domain-containing protein 1 (SORBS1) in MDSC differentiation was explored through dual luciferase activity assay, RT-qPCR, and Western blot analysis. The findings suggest that SBRT led to an increase in miR-21 levels, inhibited MDSC differentiation, and triggered cell apoptosis in BM cells. Inhibition of miR-21 reversed the effects of SBRT on MDSC differentiation and apoptosis. Additionally, it was revealed that SORBS1 was a downstream target of miR-21 in BM cells, and the miR-21/SORBS1 axis played a role in regulating MDSC differentiation and apoptosis induced by SBRT. Modulating miR-21 levels in vivo impinged on the response to SBRT treatment and the quantity of MDSCs in a mouse model of lung cancer.
CONCLUSION
Our data indicate that the upregulation of miR-21 induced by SBRT may contribute to the inhibition of MDSC expansion in a lung cancer model.
Topics: MicroRNAs; Animals; Myeloid-Derived Suppressor Cells; Radiosurgery; Mice; Lung Neoplasms; Cell Differentiation; Apoptosis; Mice, Inbred C57BL; Adaptor Proteins, Signal Transducing; Cell Line, Tumor
PubMed: 38874389
DOI: 10.1177/09603271241261307