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39057395_p24
|
39057395
|
sec[3]/p[0]
|
4. Discussion
| 4.246094 |
biomedical
|
Study
|
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The results presented in this study demonstrate that the microbial-derived product 3-IAld is able to limit the pathogenic consequences of SARS-CoV-2 infection and subsequent Aspergillus superinfection by working at multiple levels. Indeed, 3-IAld was able to limit viral replication by acting directly on the virus and to switch the host immune system from a pathogenic pro-inflammatory state to a protective antiviral response. These activities likely occur at the nasal mucosa, which represents the entry site for the virus before translocation to the lower respiratory tract. Moreover, and likely, as a consequence, 3-IAld limited the pathogenic sequelae of fungal superinfection as revealed by the controlled fungal burden and restrained inflammatory pathology in the lungs.
|
[
"Marilena Pariano",
"Anna Gidari",
"Claudia Stincardini",
"Sara Pierucci",
"Sabrina Bastianelli",
"Matteo Puccetti",
"Stefano Giovagnoli",
"Marina M. Bellet",
"Consuelo Fabi",
"Roberto Castronari",
"Cinzia Antognelli",
"Claudio Costantini",
"Maurizio Ricci",
"Daniela Francisci",
"Luigina Romani"
] |
https://doi.org/10.3390/jof10070510
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999995 |
39057395_p25
|
39057395
|
sec[3]/p[1]
|
4. Discussion
| 4.125 |
biomedical
|
Study
|
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These results confirm and extend previous findings on the role of indole derivatives containing an indole core framework to prevent and/or treat viral infections . For example, a small-molecule compound with an indole moiety was found to inhibit the main protease of SARS-CoV-2 and to block virus replication . Even more, arbidol, an indole derivative that inhibits virus entry, membrane fusion, and viral release , is approved as a prophylactic and therapeutic agent to treat influenza and other acute respiratory viral infections in Russia and China . Of interest, the anti-influenza virus activity of arbidol was comparable to that of 3-IAld . Studies have also shown that arbidol significantly contributed to both clinical and laboratory improvements in COVID-19 patients , arguing for a wide-ranging antiviral activity these compounds may have.
|
[
"Marilena Pariano",
"Anna Gidari",
"Claudia Stincardini",
"Sara Pierucci",
"Sabrina Bastianelli",
"Matteo Puccetti",
"Stefano Giovagnoli",
"Marina M. Bellet",
"Consuelo Fabi",
"Roberto Castronari",
"Cinzia Antognelli",
"Claudio Costantini",
"Maurizio Ricci",
"Daniela Francisci",
"Luigina Romani"
] |
https://doi.org/10.3390/jof10070510
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
39057395_p26
|
39057395
|
sec[3]/p[2]
|
4. Discussion
| 4.152344 |
biomedical
|
Study
|
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Our results indicate that 3-IAld works better in a prophylactic rather than therapeutic protocol. The same observation has been reported for I3C, whose antiviral activity during SARS-CoV-2 infection in Vero E6 cells was better observed in a pre-treatment protocol compared to co- and post-treatment protocols . At least in the case of 3-IAld, the reason for this result may be linked to the mechanism of action. For instance, it has been previously shown that ligands of AhR inhibited SARS-CoV-2 infection of Vero E6 cells by reducing the expression of ACE2 . Should 3-IAld, a ligand of AhR, work by means of a similar mechanism, this might explain why administration before SARS-CoV-2 infection has optimal efficacy because it would interfere with the initial steps of viral entry.
|
[
"Marilena Pariano",
"Anna Gidari",
"Claudia Stincardini",
"Sara Pierucci",
"Sabrina Bastianelli",
"Matteo Puccetti",
"Stefano Giovagnoli",
"Marina M. Bellet",
"Consuelo Fabi",
"Roberto Castronari",
"Cinzia Antognelli",
"Claudio Costantini",
"Maurizio Ricci",
"Daniela Francisci",
"Luigina Romani"
] |
https://doi.org/10.3390/jof10070510
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
39057395_p27
|
39057395
|
sec[3]/p[3]
|
4. Discussion
| 4.335938 |
biomedical
|
Study
|
[
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It is increasingly being recognized that 3-IAld can engage a variety of cellular and molecular mechanisms in the different settings in which it has been studied , some of which may be working in the protection against SARS-CoV-2 infection and subsequent Aspergillus superinfection. For instance, it has been shown that small-molecule mast cell (MC) activators may enhance immunity in the nasal mucosa and may be used as nasal vaccine adjuvants . Interestingly, 3-IAld is able to modulate the Trp metabolism in MCs and protect against autoimmune manifestations in multiple sclerosis , raising the interesting hypothesis that 3-IAld may be used to engage MCs in the nasal mucosa in vaccination strategies against COVID-19. 3-IAld could also modulate the composition and function of the microbiome. Indeed, we have previously shown that 3-IAld increases the relative abundance of pectin-degrading and sugar-degrading anaerobic bacteria resulting in increased levels of fecal SCFA and likely hydrogen sulfide (H 2 S), an end-product of the bacterial fermentation of pectin . Of note, it has been proposed that H 2 S may target SARS-CoV-2 cell entry, replication, and induction of inflammatory response . Whether 3-IAld may induce H 2 S with functional activity in the nose remains to be addressed.
|
[
"Marilena Pariano",
"Anna Gidari",
"Claudia Stincardini",
"Sara Pierucci",
"Sabrina Bastianelli",
"Matteo Puccetti",
"Stefano Giovagnoli",
"Marina M. Bellet",
"Consuelo Fabi",
"Roberto Castronari",
"Cinzia Antognelli",
"Claudio Costantini",
"Maurizio Ricci",
"Daniela Francisci",
"Luigina Romani"
] |
https://doi.org/10.3390/jof10070510
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
39057395_p28
|
39057395
|
sec[3]/p[4]
|
4. Discussion
| 4.449219 |
biomedical
|
Study
|
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The potential mechanisms engaged by 3-IAld depend on AhR activation, whose role in COVID-19 is controversial. Some studies have found that AhR is negatively correlated with SARS-CoV-2 infection and the outcome. Indeed, it was shown that AhR is activated by an IFNβ or IFNγ/indoleamine 2,3-dioxygenase (IDO)1/kynurenine (kyn) pathway in alveolar epithelial cells to increase the expression of mucins and induce hypoxia . In addition, AhR activation promoted SARS-CoV-2 infection and replication, limited type I IFN signaling, and up-regulated the expression of ACE2, thus acting as a proviral factor whose inhibition was suggested to be used as a therapeutic approach in COVID-19. At variance with these studies, a repurposing screen identified Phortress, an AhR-activating ligand, as an antiviral candidate for both an Alpha- and a Beta-coronavirus . Similarly, as previously mentioned, AhR activation decreased the ACE2 expression and SARS-CoV-2 infection of Vero E6 cells . This is in line with the antiviral activity of AhR agonists against Influenza A virus and the protection against Acute Respiratory Distress Syndrome . We have similarly found that AhR activation by 3-IAld was associated with type I IFN production and interference with SARS-CoV-2 replication in nasal cells and VeroE6 cells.
|
[
"Marilena Pariano",
"Anna Gidari",
"Claudia Stincardini",
"Sara Pierucci",
"Sabrina Bastianelli",
"Matteo Puccetti",
"Stefano Giovagnoli",
"Marina M. Bellet",
"Consuelo Fabi",
"Roberto Castronari",
"Cinzia Antognelli",
"Claudio Costantini",
"Maurizio Ricci",
"Daniela Francisci",
"Luigina Romani"
] |
https://doi.org/10.3390/jof10070510
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999995 |
39057395_p29
|
39057395
|
sec[3]/p[5]
|
4. Discussion
| 4.496094 |
biomedical
|
Study
|
[
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The different ligand- and tissue-specific activities of AhR may account for these discrepancies. For instance, it was shown that 3-IAld could limit graft-versus-host disease (GvHD) by activating type I IFN signaling , consistent with the notion that not only the diversity of the ligands, but also the context in which AhR is activated may direct downstream signaling pathways. An inflammatory GvHD may redirect AhR activation towards type I IFN signaling while an antiviral background response may instead promote an AhR-mediated inflammatory signaling, thus making AhR a regulatory node to balance between the two responses. Tissue-specific differences in the expression and activation of AhR, and of AhR ligands as well, in the lower and higher respiratory tract may also be involved. For instance, scRNA studies in the respiratory tract have shown that IDO1 is most expressed in the nose and belongs to the immune genes over-represented in the top ACE2-correlated genes . In agreement with these studies, our results on Trp metabolites in hematological patients indicate that the nose had higher levels of kyn compared with the pharynx . This might suggest that in a background of high IDO1 activity, such as in the nose, AhR may be more responsive to the action of different ligands compared to the lungs where the levels of kyn are lower. Thus, at variance with the nose, the increased kyn levels in the lung upon viral-induced IFN signaling may activate AhR to promote a pro-inflammatory response. Should such a scenario prove to be plausible, AhR antagonists might prove more effective for local targeting into the lungs rather than for constraining AhR activity across the entire respiratory tree.
|
[
"Marilena Pariano",
"Anna Gidari",
"Claudia Stincardini",
"Sara Pierucci",
"Sabrina Bastianelli",
"Matteo Puccetti",
"Stefano Giovagnoli",
"Marina M. Bellet",
"Consuelo Fabi",
"Roberto Castronari",
"Cinzia Antognelli",
"Claudio Costantini",
"Maurizio Ricci",
"Daniela Francisci",
"Luigina Romani"
] |
https://doi.org/10.3390/jof10070510
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
39057395_p30
|
39057395
|
sec[3]/p[6]
|
4. Discussion
| 4.058594 |
biomedical
|
Study
|
[
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In conclusion, our results shed new light on the potential role of AhR in COVID-19 by virtue of its promiscuity of ligands and activities, and specifically put forward the hypothesis that microbial compounds, such as 3-IAld, owing to their multiplicity of activities and favorable safety profile , may be used as prophylactic agents in the protection against viral colonization and infection, and subsequent fungal superinfection.
|
[
"Marilena Pariano",
"Anna Gidari",
"Claudia Stincardini",
"Sara Pierucci",
"Sabrina Bastianelli",
"Matteo Puccetti",
"Stefano Giovagnoli",
"Marina M. Bellet",
"Consuelo Fabi",
"Roberto Castronari",
"Cinzia Antognelli",
"Claudio Costantini",
"Maurizio Ricci",
"Daniela Francisci",
"Luigina Romani"
] |
https://doi.org/10.3390/jof10070510
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11278182_p0
|
PMC11278182
|
sec[0]/p[0]
|
1. Introduction
| 4.417969 |
biomedical
|
Study
|
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Nitrogen plays an indispensable role in the growth and development of microalgae, existing in various forms in the marine environment, such as dissolved inorganic nitrogen, dissolved organic nitrogen, and particulate nitrogen. Different nitrogen sources significantly impact the absorption and utilization efficiency of microalgae . Urea, a commonly used nitrogen source in microalgae cultivation, stands out for its ability to provide both organic carbon and nitrogen . Subsequently, urea affects protein synthesis, photosynthesis, cell division and growth, and biomass accumulation. Researchers have conducted extensive studies on the impact of urea concentration on biological growth. For instance, it has been demonstrated that microalgae exhibit a higher rate of absorption and utilization of urea compared to inorganic nitrogen sources . Maintaining an appropriate concentration of organic nitrogen is essential. Organic nitrogen influences the cell cycle, quiescence, and the accumulation of triacylglycerol (TAG) in algal cells. Therefore, urea, which can provide organic nitrogen, is a crucial nitrogen source for algal cells . According to Ali Nawaz Kumbhar’s research, minimal urea supply promotes the highest production of total and neutral lipids in Chlorella pyrenoidosa compared to high urea concentrations . However, excessive nitrogen concentrations, particularly ammonium ions, can accumulate inside cells, leading to PSII damage and impacting the photosynthetic process. For example, urea affects lutein production; optimal urea addition increases biomass and lutein content, while excessive urea negatively affects growth and lutein synthesis . Despite urea’s evident impact on the physiological and ecological aspects of microalgae, the precise molecular mechanisms affected remain unclear.
|
[
"Han Zhu",
"Zhenli Ye",
"Zhengru Xu",
"Li Wei"
] |
https://doi.org/10.3390/life14070797
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11278182_p1
|
PMC11278182
|
sec[0]/p[1]
|
1. Introduction
| 4.417969 |
biomedical
|
Study
|
[
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Nannochloropsis oceanica, a single-cell green microalga, holds great promise as a biological resource for biofuel and pharmaceutical production. This small green microalga is renowned for its rich composition of photosynthetic pigments, proteins, and polyunsaturated fatty acids, particularly eicosapentaenoic acid (EPA). N. oceanica is widely utilized as a model organism, characterized by its rapid growth, excellent photosynthetic efficiency, and high lipid accumulation . Under nitrogen stress, algal growth is limited, usually manifested as a lower biomass growth rate and smaller cell size. This reduction in biomass growth rate and cell size leads to a decrease in chlorophyll content, affecting chlorophyll fluorescence and photosynthetic efficiency. Additionally, algae may adopt various adaptation mechanisms to reduce unnecessary consumption and conserve nitrogen resources . N. oceanica is highly sensitive to nitrogen and other nutrient elements, and its growth and metabolism require an adequate supply of nitrogen. Adding 2 g/L of urea to the culture medium significantly promotes the growth of N. oceanica under conditions of 25 °C and 5% CO 2 . By using urea at different concentration gradients as a nitrogen source at varying rates, it could increase the protein and fat content, as well as essential amino acids and fatty acid content in N. oceanica . A higher cell count in N. oceanica was observed, which indicates that the growth of this microalgae can be promoted by urea. However, the impact of urea on lipid content was relatively small . Compared to other nitrogen sources (NaNO 3 , NH 4 NO 3 , NH 4 HCO 3 , (NH 4 ) 2 SO 4 ), N. oceanica cultivated with urea had lower lipid content . However, reducing the urea concentration to 0.2 g/L inhibits cell growth. Under urea-limiting conditions, it may adjust its nitrogen metabolism to adapt to the environment. As mentioned above, urea stress inhibits photosynthesis but is conducive to the formation of oils. Urea can regulate the nitrogen metabolism of microalgae, influencing their lipid accumulation. These different metabolic strategies of N. oceanica under urea addition are worth exploring.
|
[
"Han Zhu",
"Zhenli Ye",
"Zhengru Xu",
"Li Wei"
] |
https://doi.org/10.3390/life14070797
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11278182_p2
|
PMC11278182
|
sec[0]/p[2]
|
1. Introduction
| 4.273438 |
biomedical
|
Study
|
[
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[
0.99951171875,
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In this study, we will explore the effects of different nitrogen nutrition conditions (with and without the addition of urea; NaNO 3 + urea or NaNO 3 ) on the growth of N. oceanica through two experimental groups and apply mRNA-seq to reveal the molecular response. Transcriptome analysis revealed that the addition of urea led to differential expression of 2104 genes in the experimental group (NaNO 3 + urea; U) compared to the control group (NaNO 3 ; Ct). The result indicated a significant downregulation of photosynthesis-related genes in microalgae, especially genes related to light-harvesting protein. Interestingly, the absorption and transport of urea may not only rely on a specialized transport mechanism mediated by urease but also alternative transport channels such as the ABC transporter family, and CLC protein family. Adenosine is deaminated to form inosine. Inosine is hydrolyzed to produce hypoxanthine and ribose. Hypoxanthine is further oxidized by xanthine oxidase to form xanthine, which is then oxidized to uric acid . Among these steps, we found that only the expression of purine nucleoside phosphorylase was significantly downregulated, with a fold change of 2.48 in N. oceanica under Ct vs. U . Additionally, urea induced specific changes in carbon metabolism and lipid metabolism. Genes related to the Calvin cycle and carbon concentration mechanisms were significantly upregulated. In lipid metabolism, genes associated with lipases or polyunsaturated fatty acid enzymes were highly activated. Furthermore, there was enhanced expression in the tricarboxylic acid cycle and folate metabolism, contributing significantly to energy supply and the synthesis and modification of genes or large biomolecules.
|
[
"Han Zhu",
"Zhenli Ye",
"Zhengru Xu",
"Li Wei"
] |
https://doi.org/10.3390/life14070797
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11278182_p3
|
PMC11278182
|
sec[1]/sec[0]/p[0]
|
2.1. Culture Conditions of N. oceanica
| 4.195313 |
biomedical
|
Study
|
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N. oceanica IMET1 cells were inoculated into modified f/2 liquid medium containing 30 g/L sea salt, 1 g L −1 NaNO 3 , 3.65 mg L −1 FeCl 3 *6H 2 O, 67 mg L −1 NaH 2 PO 4 *H 2 O, 4.37 mg L −1 Na 2 EDTA*2H 2 O, trace metal mix , and vitamin mix (2.5 µg L −1 biotin, 2.5 µg L −1 VB 12 , and 0.5 µg L −1 thiamine HCl), and 100mM Tris-HCl (pH = 7.8) . Microalgal cells were cultivated in f/2 medium under continuous irradiation (light intensity: 50 ± 5 μmol m −2 s −1 ) at 25 °C in a 1 L column reactor (inner diameter: 5 cm). During the logarithmic growth phase (OD 750 = 3.0), cells were harvested via 5000 rpm centrifugation. Subsequently, the microalgae cells were washed three times with nitrogen-free sterile seawater. One batch was cultured in a medium supplemented with sodium nitrate (as a control group: Ct) at an inoculation density of OD 750 = 0.46. Another batch was cultured in a medium supplemented with both sodium nitrate and urea (the final urea density of urea addition 2g/L; as an experimental group: U) with OD 750 = 0.46, and physiological parameters were measured. After transfer to two fresh-medium conditions at 72 h, cell aliquots from the urea addition samples (U) and control group (Ct) were collected for RNA isolation, with three replicates. Fv/Fm (the variable/maximum fluorescence ratio), the maximum photochemical quantum yield of PSII reaction centers, represents the minimum fluorescence yield when PSII reaction centers are fully open and reflects the photosynthetic light energy conversion efficiency. This parameter was measured using AquaPen AP110-C. To quantify the amounts of carbohydrate, protein, and lipid, N. oceanica cells were harvested after 14 days of cultivation by centrifugation at 4000 rpm for 5 min under both Ct and U conditions. The harvested cells were then lyophilized for two days to obtain dried algal powder. The extraction and quantification of lipids, carbohydrates, and proteins from the microalgal biomass were carried out according to our previously published protocols. The physiological data for each time point are presented as mean values with standard deviations. One-way ANOVA was applied to compare the growth rates across different conditions and time points.
|
[
"Han Zhu",
"Zhenli Ye",
"Zhengru Xu",
"Li Wei"
] |
https://doi.org/10.3390/life14070797
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11278182_p4
|
PMC11278182
|
sec[1]/sec[1]/p[0]
|
2.2. Total RNA Extraction
| 4.109375 |
biomedical
|
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|
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RNA extraction from microalgal cells involved the use of TRIzol ® Re-agent and chloroform following Li’s protocols (Invitrogen, Carlsbad, CA, USA). Genomic DNA elimination was achieved using DNase I (TaKara) . Subsequently, the 2100 Bioanalyzer (Agilent Technologies, Inc., Santa Clara, CA, USA) assessed the integrity and purity of the total RNA, while quantification was performed with the ND-2000 (NanoDrop Thermo Scientific, Wilmington, DE, USA) and Qubit 3.0 (Life Technologies, Carlsbad, CA, USA). Only high-quality RNA samples meeting the criteria of OD260/280 = 1.8~2.2 and OD260/230 ≥ 2.0 were selected for the construction of the sequencing library.
|
[
"Han Zhu",
"Zhenli Ye",
"Zhengru Xu",
"Li Wei"
] |
https://doi.org/10.3390/life14070797
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999994 |
PMC11278182_p5
|
PMC11278182
|
sec[1]/sec[2]/p[0]
|
2.3. Illumina Novaseq 6000 Sequencing and mRNA Sequencing Library Preparation
| 4.222656 |
biomedical
|
Study
|
[
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RNA purification, reverse transcription, library construction, and sequencing were conducted at Shanghai Majorbio Bio-pharm Biotechnology Co., Ltd. (Shanghai, China), following the guidelines of the Illumina manufacturer (San Diego, CA, USA). The creation of the four mRNA-seq libraries utilized the Illumina TruSeq TM RNA Sample Preparation Kit (San Diego, CA, USA). Initial steps involved total RNA purification and isolation using oligo-dT-attached magnetic beads, followed by RNA fragmentation with a fragmentation buffer. Subsequently, short RNA fragments served as templates for double-stranded cDNA synthesis using the SuperScript Double-Stranded cDNA Synthesis Kit (Invitrogen, Carlsbad, CA, USA) with random hexamer primers. The synthesized double-stranded cDNA underwent end-repair, phosphorylation, and “A” base addition as per Illumina’s library construction protocol. Target fragments of 200–300 bp were selected, and libraries were run on 2% Low Range Ultra Agarose post PCR-amplification using Phusion DNA Polymerase (New England Biolabs, Boston, MA, USA) for fifteen cycles. After quantification, the four RNA sequencing libraries underwent sequencing in a single lane on an Illumina NovaSeq 6000 platform (Illumina, San Diego, CA, USA) for 2 × 150 bp paired-end reads.
|
[
"Han Zhu",
"Zhenli Ye",
"Zhengru Xu",
"Li Wei"
] |
https://doi.org/10.3390/life14070797
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11278182_p6
|
PMC11278182
|
sec[1]/sec[3]/p[0]
|
2.4. Transcriptome Assembly and Functional Annotation
| 4.253906 |
biomedical
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0.00008118152618408203
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The raw paired-end reads of mRNA-seq were trimmed and data quality was controlled using software of SeqPrep and Sickle with default parameters. Then clean data from the samples (Ct) were employed to perform de novo assembly with Trinity . All the assembled transcripts were searched against the protein nonredundant (NR) of NCBI, String, and KEGG databases using BLASTX to identify the proteins that had the highest sequence similarity with the given transcripts to retrieve their function annotations and a typical cut-off E-values less than 1.0 × 10 −5 was set. BLAST2GO program was used to obtain GO annotations of unique assembled transcripts for describing biological processes, molecular functions, and cellular components. Metabolic pathway analysis was performed using the KEGG (Kyoto Encyclopedia of Genes and Genomes) . Raw sequencing data are assessed for quality using FastQC and then subjected to quality trimming using Trimmomatic, resulting in relatively accurate and valid data. Clean data are assembled into transcripts de novo using Trinity . The effective data from the samples are subjected to mixed splicing assembly, resulting in transcripts, and the sequence length and GC content of the assembled sequences are counted. The assembled transcripts are used as a reference sequence, and the sequencing data are compared and analyzed against them to filter sequencing sequences that can be mapped to the reference sequence.
|
[
"Han Zhu",
"Zhenli Ye",
"Zhengru Xu",
"Li Wei"
] |
https://doi.org/10.3390/life14070797
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11278182_p7
|
PMC11278182
|
sec[1]/sec[4]/p[0]
|
2.5. Differential Expression Analysis and Functional Enrichment Analysis
| 4.167969 |
biomedical
|
Study
|
[
0.99951171875,
0.0002906322479248047,
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] |
[
0.9990234375,
0.0002155303955078125,
0.000545501708984375,
0.00007289648056030273
] |
Identification of differentially expressed genes (DEGs) between two distinct samples involved analyzing the expression levels of individual transcripts using the Fragments Per Kilobase of Exon Per Million Mapped Reads (FPKM) method. Quantification of gene and isoform abundances was performed using the RSEM tool . The R statistical package software EdgeR (Empirical Analysis of Digital Gene Expression in R, facilitated the differential expression analysis . Furthermore, functional enrichment analysis, encompassing Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG), was conducted. This aimed to identify DEGs significantly enriched in GO terms and metabolic pathways at a Bonferroni-corrected p -value ≤ 0.05 when compared with the entire transcriptome background. The GO functional enrichment and KEGG pathway analysis were carried out using two software tools, namely Goatools and KOBAS .
|
[
"Han Zhu",
"Zhenli Ye",
"Zhengru Xu",
"Li Wei"
] |
https://doi.org/10.3390/life14070797
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11278182_p8
|
PMC11278182
|
sec[1]/sec[4]/p[1]
|
2.5. Differential Expression Analysis and Functional Enrichment Analysis
| 3.59375 |
biomedical
|
Other
|
[
0.99462890625,
0.0005788803100585938,
0.004589080810546875
] |
[
0.09039306640625,
0.9033203125,
0.0058135986328125,
0.0003936290740966797
] |
Typically, the Pearson correlation coefficient is used as an evaluation metric for replicative correlation , and the closer the coefficient value is to 1, the higher the similarity of expression characteristics between samples.
|
[
"Han Zhu",
"Zhenli Ye",
"Zhengru Xu",
"Li Wei"
] |
https://doi.org/10.3390/life14070797
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11278182_p9
|
PMC11278182
|
sec[1]/sec[4]/p[2]
|
2.5. Differential Expression Analysis and Functional Enrichment Analysis
| 4.171875 |
biomedical
|
Study
|
[
0.99951171875,
0.0001628398895263672,
0.00020420551300048828
] |
[
0.9951171875,
0.002780914306640625,
0.0018644332885742188,
0.00010710954666137695
] |
The volcano plot is the most commonly used method to display the results of differential gene expression analysis. It uses a t -test to analyze genes with significant differential expression between two samples, with log 2 (fold change) on the x-axis and the negative logarithm −log10 (q-value) of the p -value from the t -test on the y-axis. The volcano plot includes two important metrics: fold change and adjusted q-value. Each point on the plot represents a gene, with colors used to differentiate whether genes are differentially expressed. In the control group, there are 212 unique genes, accounting for 2.24% of the total genes. In the experimental group, there are 197 unique genes, making up 2.08% of the total genes. There are 9051 genes shared between the two groups, representing 95.68% of the total genes.
|
[
"Han Zhu",
"Zhenli Ye",
"Zhengru Xu",
"Li Wei"
] |
https://doi.org/10.3390/life14070797
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11278182_p10
|
PMC11278182
|
sec[1]/sec[5]/p[0]
|
2.6. qPCR Experiment for Validating mRNA-seq
| 4.085938 |
biomedical
|
Study
|
[
0.99951171875,
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[
0.99951171875,
0.0002524852752685547,
0.0002143383026123047,
0.00005346536636352539
] |
To minimize bias stemming from different biological replicates, six genes were selected for RT-qPCR analysis. The same samples used in mRNA-seq experiment were employed for RT-qPCR. The M-MLV Reverse Transcription Kit (Promega, Madison, WI, USA) was used to synthesize cDNA following the manufacturer’s instructions. Gene-specific primers ( Table S1 ) were designed using Primer5 software (Primer Premier 5.0). A 20 μL reaction mixture was prepared using the SYBR Green qPCR Kit Master Mix (Roche, South San Francisco, CA, USA) and run on the real-time PCR LifeCycle480 system (Roche, USA) according to the manufacturer’s protocol. The cycle threshold value (CT) and differential expression fold change were calculated based on the 2 −ΔΔCT method with the actin gene of N. oceanica IMET1 as the endogenous reference. Each sample was run in triplicate to confirm the reproducibility of the results.
|
[
"Han Zhu",
"Zhenli Ye",
"Zhengru Xu",
"Li Wei"
] |
https://doi.org/10.3390/life14070797
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11278182_p11
|
PMC11278182
|
sec[2]/sec[0]/p[0]
|
3.1. Physiological Changes after Urea Addition
| 4.105469 |
biomedical
|
Study
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[
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] |
To survey the impact of urea addition on growth, the physiological responses of N. oceanica IMET1 were tracked under two contrasting culture conditions: NaNO 3 (Ct: control) and NaNO 3 + urea (U: experimental group, with a final urea concentration of 2 g/L). In this experiment, the growth of microalgae was assessed by measuring the optical density (OD) of the algal culture using a spectrophotometer. After a 14-day cultivation period, we found that the growth of the urea-added group was significantly faster than that of the control group on the third day. However, there were no significant differences in the growth of microalgae between the control group and the experimental group from the fifth to the eighth day . After the eighth day, the growth of the experimental group displayed a slight increase compared to the control group . However, the urea addition did not result in a statistically significant increase in growth. Thus, we conclude that urea treatment did not negatively affect the growth of N. oceanica cells.
|
[
"Han Zhu",
"Zhenli Ye",
"Zhengru Xu",
"Li Wei"
] |
https://doi.org/10.3390/life14070797
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11278182_p12
|
PMC11278182
|
sec[2]/sec[1]/sec[0]/p[0]
|
3.2.1. Transcriptome Data of N. oceanica from Illumina Sequencing
| 4.066406 |
biomedical
|
Study
|
[
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[
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] |
TPM (Transcripts Per Million) is a common method for estimating gene expression levels, which considers the true expression level of genes, gene length, and sequencing depth’s impact on reads counting . The correlation of gene expression between samples is an important indicator for assessing the reliability of experiments and the rationality of sample selection . In addition, qPCR was performed to validate mRNA-seq data, and the results demonstrated the quality of mRNA-seq was reliable for further analysis .
|
[
"Han Zhu",
"Zhenli Ye",
"Zhengru Xu",
"Li Wei"
] |
https://doi.org/10.3390/life14070797
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11278182_p13
|
PMC11278182
|
sec[2]/sec[1]/sec[0]/p[1]
|
3.2.1. Transcriptome Data of N. oceanica from Illumina Sequencing
| 4.097656 |
biomedical
|
Study
|
[
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[
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0.0000489354133605957
] |
Based on the correlation analysis Heatmap chart of the six samples, the correlation among the three replicates in the control group (Ct1, Ct2, Ct3) ranges from 0.993 to 1, while in the experimental group (U1, U2, U3), the correlation among the three replicates falls between 0.986 and 1. The strong correlation within each group confirms the reliability of the data quality and indicates that it can be used for further analysis. To further elaborate on these findings, the high correlation values suggest a high degree of consistency and reproducibility among the biological replicates within each group. This level of reproducibility is crucial for ensuring that observed differences between control and experimental conditions are due to the experimental treatment rather than variability in sample processing or measurement errors .
|
[
"Han Zhu",
"Zhenli Ye",
"Zhengru Xu",
"Li Wei"
] |
https://doi.org/10.3390/life14070797
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11278182_p14
|
PMC11278182
|
sec[2]/sec[1]/sec[1]/p[0]
|
3.2.2. Sample Correlation Analysis Inter-Sample Venn Analysis and Differentially Gene Expression Analysis by the Volcano Plot
| 4.015625 |
biomedical
|
Study
|
[
0.99951171875,
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[
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] |
The upregulated genes exhibited a higher fold change in expression compared to the downregulated genes, and the differential expression of upregulated genes was more pronounced than that of downregulated genes. Differentially expressed genes were identified using DESeq in R, with filtering criteria set to q-value < 0.05 and |fold change| > 2 .
|
[
"Han Zhu",
"Zhenli Ye",
"Zhengru Xu",
"Li Wei"
] |
https://doi.org/10.3390/life14070797
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11278182_p15
|
PMC11278182
|
sec[2]/sec[1]/sec[1]/p[1]
|
3.2.2. Sample Correlation Analysis Inter-Sample Venn Analysis and Differentially Gene Expression Analysis by the Volcano Plot
| 3.830078 |
biomedical
|
Study
|
[
0.9990234375,
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[
0.9990234375,
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] |
The differential gene expression analysis between the urea-added group and the urea-free group of the marine microalgae Nannochloropsis oceanica revealed a total of 2104 differentially expressed genes. Among these, 1354 genes were upregulated, while 750 genes were downregulated .
|
[
"Han Zhu",
"Zhenli Ye",
"Zhengru Xu",
"Li Wei"
] |
https://doi.org/10.3390/life14070797
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11278182_p16
|
PMC11278182
|
sec[2]/sec[1]/sec[2]/p[0]
|
3.2.3. Functional Enrichment of Differential Expressed Gene by GO and KEGG
| 4.21875 |
biomedical
|
Study
|
[
0.99951171875,
0.0003082752227783203,
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] |
[
0.9990234375,
0.00015735626220703125,
0.0005812644958496094,
0.00006031990051269531
] |
Gene ontology classification annotation was performed on the obtained genes, as shown in Figure 3 . From the graph, we can observe that the majority of genes are annotated to the cellular component category, while the differences in genes annotated to biological processes and molecular functions are less pronounced. Within the biological process category, there are a total of six enriched functions, including “response to stimulus”, “cellular component organization or biogenesis”, “localization”, “biological regulation”, “metabolic process” and “cellular process”. Among these, “metabolic process” and “cellular process” show significant enrichment, each category encompassing approximately 600 genes. In the cellular component category, the affected parts include “cell”, “membrane”, “organelle part”, “protein-containing complex”, “organellecell part” and “membrane part”. Notably, the “single-cell part” and “membrane part” exhibit the most significant differential gene enrichment, with approximately 600 and 850 genes enriched, respectively. In the molecular function category, the functions associated with differentially expressed genes include “molecular regulator activity”, “transcription regulator activity”, “translation regulator activity”, “structural molecule activity”, “transporter activity”, “binding” and “catalytic activity”. Differential gene enrichment is particularly pronounced in the “binding” and “catalytic activity’ functions”, with approximately 800 and 900 genes enriched in these categories, respectively .
|
[
"Han Zhu",
"Zhenli Ye",
"Zhengru Xu",
"Li Wei"
] |
https://doi.org/10.3390/life14070797
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11278182_p17
|
PMC11278182
|
sec[2]/sec[1]/sec[2]/p[1]
|
3.2.3. Functional Enrichment of Differential Expressed Gene by GO and KEGG
| 4.324219 |
biomedical
|
Study
|
[
0.99951171875,
0.0003192424774169922,
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[
0.998046875,
0.0003368854522705078,
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0.00009822845458984375
] |
After performing KEGG annotation on differentially expressed genes and classifying KEGG metabolic pathways based on the connections between KEGG and pathways, they are mainly divided into five categories: environment information processing (this category includes two pathways: membrane transport and signal transduction), human diseases (includes two pathways: endocrine and metabolic diseases and infectious diseases: parasitic), cellular processes (under this category, there are pathways related to the metabolism of terpenoids and polyketides), metabolism (this category encompasses ten pathways: biosynthesis of other secondary metabolites, glycan biosynthesis and metabolism, nucleotide metabolism, metabolism of other amino acids, metabolism of cofactors and vitamins, lipid metabolism, transport and catabolism, energy metabolism, carbohydrate metabolism, and amino acid metabolism), genetic information processing (four pathways: transcription, folding, sorting, and degradation, replication and repair, and translation). In terms of metabolic functions, the highest enrichment of differentially expressed genes is observed, especially in carbohydrate metabolism pathways, where 68 genes are enriched. Most of these genes involved in controlling photosynthetic carbon fixation are upregulated. Additionally, differential gene enrichment in lipid metabolism pathways is also noticeable, with 35 genes enriched .
|
[
"Han Zhu",
"Zhenli Ye",
"Zhengru Xu",
"Li Wei"
] |
https://doi.org/10.3390/life14070797
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999995 |
PMC11278182_p18
|
PMC11278182
|
sec[2]/sec[2]/p[0]
|
3.3. Nitrogen Metabolism Affected by Urea Addition in N. oceanica
| 4.425781 |
biomedical
|
Study
|
[
0.9990234375,
0.00046539306640625,
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[
0.9990234375,
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0.00042700767517089844,
0.00011718273162841797
] |
To study the impact of urea addition on nitrogen metabolism, we analyzed the main pathways of nitrogen assimilation. Upon annotating the transcriptome three genes (urea/Na+ high-affinity symporter, nitrate high-affinity transporter, and ammonium transporter) related to nitrogen transporter exhibited significant downregulation . Among them, urea/Na+ high-affinity symporter involved in the urea transport process, downregulated by a fold change of 13.33 under Ct vs. U. Under urea-added cultivation conditions, N. oceanica tends to preferentially utilize NH 4 + . However, the transcriptional expression of the ammonium transporter gene differs significantly from the expected pattern. This preference may be mediated through a low-affinity ammonium transport protein system (LATS) . In addition, nitrate high-affinity transporter is responsible for nitrate absorption and transport, showing a 9.36-fold downregulation in the experimental group. Ammonium transporter is a type of NH 4 + transport protein responsible for the transport of NH 4 + within organisms. Under Ct vs. U, the expression of this ammonium transport protein was downregulated by 21.74-fold. The ammonium transporter gene possesses a conserved C-terminal regulatory domain and a highly protein homologous structure. It can form trimers by binding with other related monomeric transport proteins to facilitate the transport of NH 4 + . Additionally, studies indicate that the conserved C-terminal regulatory domain of the ammonium transporter protein is regulated by phosphorylation at two threonine residues, T460 and T472 . When the external NH 4 + concentration is low, the phosphorylation state of the serine residues at the C-terminal region determines whether dephosphorylation occurs, thereby influencing NH 4 + absorption or inhibition .
|
[
"Han Zhu",
"Zhenli Ye",
"Zhengru Xu",
"Li Wei"
] |
https://doi.org/10.3390/life14070797
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11278182_p19
|
PMC11278182
|
sec[2]/sec[2]/p[1]
|
3.3. Nitrogen Metabolism Affected by Urea Addition in N. oceanica
| 4.496094 |
biomedical
|
Study
|
[
0.9990234375,
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[
0.9990234375,
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] |
Nitroreductase-like protein is involved in the reduction of nitrite to ammonia or other nitrogen compounds, and its expression level has decreased by 28.57-fold . Ferredoxin nitrite reductase is also involved in the nitrate reduction metabolic pathway, converting nitrate into nitrite. However, based on the provided data, its expression level is downregulated by 17.54-fold . This phenomenon indicates the inhibition of the nitrogen absorption pathway for nitrate. In general, urea is absorbed by algae through two pathways: urease or ureamide hydrolase (DUR) degradation to produce ammonia, which is subsequently converted to other forms of nitrogen via the GS cycle . It has been reported that urease activity in algal cells is regulated by nitrogen species in the culture environment . Urea and NO 3 − can enhance it, and NH 4 + can inhibit it. Interestingly, it was found that the expression of the Dur3 gene under different nitrogen source conditions was also affected by nitrogen source type, and the addition of urea and NH 4 + inhibited the expression of the Dur3 gene . In addition, some prokaryotes, such as Cyanobacteria , can also be driven to take up urea by ABC binding box (ATP-binding protein) transporters . Research has shown that the expression of various nitrogen transport proteins and auxiliary proteins in the experimental group is significantly downregulated. This observed downregulation occurs in Arabidopsis , wheat seedlings, and various algae . However, we note that the transcriptional levels of some possible low-affinity transport channels are significantly upregulated. This suggests that algae may employ various nitrogen transfer mechanisms to accomplish the absorption of nitrogen sources . The expression of some ABC protein families is significantly upregulated ( Dataset S1 ). This may indicate the involvement of ABC protein families in the transport of urea in N. oceanica . These protein families typically involve ATP binding and hydrolysis to facilitate the transmembrane transport of substances . In addition, Chloride Channel Protein 7 is a member of the CLC protein family, and it exhibits a significant upregulation at the mRNA level with a fold change of 3.67 ( Dataset S1 ). CLC transport proteins belong to the nitrate transporter protein family. Previously, it has been discovered that CLCa and chloroplast-localized CLCe cooperatively participate in the assimilation process of nitrate nitrogen . In N. oceanica , Chloride Channel Protein 7 might perform the same function.
|
[
"Han Zhu",
"Zhenli Ye",
"Zhengru Xu",
"Li Wei"
] |
https://doi.org/10.3390/life14070797
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11278182_p20
|
PMC11278182
|
sec[2]/sec[2]/p[2]
|
3.3. Nitrogen Metabolism Affected by Urea Addition in N. oceanica
| 4.453125 |
biomedical
|
Study
|
[
0.9990234375,
0.0005283355712890625,
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[
0.9990234375,
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] |
At the same time, we found that the GS/GOGAT cycle is highly activated, and the genes for aspartate synthetase and its associated amino acids (such as serine, tryptophan, and nucleotides) are significantly upregulated at the transcriptional level. This indicates that nitrogen utilization and transfer as well as amino acid anabolism are active under urea addition. In Arabidopsis , urea-derived ammonia is converted into glutamine, and then further synthesized into glutamate by the GS/GOGAT cycle. This indicates that the addition of urea promotes the activity of the GS/GOGAT cycle . There is significant activity in both ammonia assimilation and ammonia dissimilation. For instance, in the direction of ammonia assimilation, the expression of gene delta-1-pyrroline-5-carboxylate synthetase is upregulated by 6.46-fold, gene kynureninase is upregulated by 177.16-fold, and gene asparagine synthase is upregulated by 63.69-fold ( Table 1 ). These genes are involved in the synthesis and metabolism of amino acids. Regarding ammonia dissimilation, the gene (g615) encodes uricase, which is involved in uric acid metabolism, while the function of gene putative urate catabolism protein is suspected to be related to uric acid breakdown metabolism ( Table 1 ). the genes encoded urate oxidase and putative urate catabolism protein each show an upregulation of about 2-fold at the mRNA level. As for the urea cycle, although there were no detected differential expressions in the genes encoding Ornithine Transcarbamylase (OTC) and Argininosuccinate Lyase (ASL), the gene expression of argininosuccinate synthase showed a substantial upregulation (2.12-fold) ( Dataset S1 ). Argininosuccinate synthase plays a crucial role in the synthesis of argininosuccinate from citrulline and aspartate, a key step in the conversion of arginine to urea in the urea cycle. This upregulation may indicate a cellular response to increased demand for argininosuccinate or enhanced urea cycle activity. These indicate that in response to additional urea supply, N. oceanica adopted a series of regulatory reactions to maintain the balance of nitrogen metabolism. These regulatory reactions include that conventional nitrogen transporters are inhibited and may turn to low-affinity transport channels to enhance nitrogen utilization and transfer through amino acid synthesis and metabolism. In the physiological data measurements, the total amount of protein measured in the experimental group was higher than that in the control group, which provides corroborative evidence .
|
[
"Han Zhu",
"Zhenli Ye",
"Zhengru Xu",
"Li Wei"
] |
https://doi.org/10.3390/life14070797
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11278182_p21
|
PMC11278182
|
sec[2]/sec[3]/p[0]
|
3.4. Change in Photosynthesis in Response to Urea Addition
| 4.441406 |
biomedical
|
Study
|
[
0.9990234375,
0.0005769729614257812,
0.00036597251892089844
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[
0.9990234375,
0.00027680397033691406,
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0.00013494491577148438
] |
In order to explore whether urea addition has an effect on photosynthesis, we conducted a detailed analysis of transcripts related to the photosystem I and II, and chlorophyll biosynthesis genes in N. oceanica . The presence of urea significantly downregulates the expression of genes associated with both the light-harvesting complex proteins (LHC) and photosystem proteins. Notably, most LHC genes uniquely showed a 2.0~2.5-fold downregulation at the transcript level ( Table 2 ). Additionally, other genes encoded (cytochrome c biogenesis protein, thiol reduction transmembrane region) also displayed significant downregulation, which indicates potential inhibition of photosynthetic activity occurred in N. oceanica . In fact, we measured the photosynthetic parameter Fv/Fm. The results showed that, over time, the Fv/Fm values of the experimental group with urea addition gradually decreased. This confirms that the addition of urea may have an inhibitory effect on N. oceanica photosynthetic efficiency . In a previous study, ammonium limitation in algal cultivation may impair photosynthesis by damaging the photosystem or uncoupling photophosphorylation with electron transport . Furthermore, the addition of urea in Gracilariopsis lemaneiformis led to a decrease in photosynthetic pigment proteins, potentially prioritizing the degradation of these proteins during urea substitution, serving as a strategy for rapid restructuring and balancing nitrogen metabolism in algal cells . On the other hand, reducing pigment content in plants can improve water and nitrogen utilization efficiency , supported by studies showing an increase in biomass in photosynthetic organisms through reduced pigment content . Additionally, we observed an upregulation of the expression of cytochrome b6-f complex iron–sulfur subunit by 2.42-fold at the mRNA level ( Table 2 ). This complex is crucial in the chloroplast, participating in electron transport and proton pumping during photosynthesis . The upregulation of iron–sulfur assembly-like protein and ribulose-phosphate 3-epimerase suggests adaptations to different growth conditions and photosynthetic requirements under urea + NaNO 3 or NaNO 3 ( Table 2 ). These observations indicate that urea likely hydrolyzed to produce CO 2 and participates in the carbon concentrating mechanism (CCM) as a new carbon source, optimizing nitrogen supply and prompting N. oceanica to adjust its photosynthetic carbon fixation strategy.
|
[
"Han Zhu",
"Zhenli Ye",
"Zhengru Xu",
"Li Wei"
] |
https://doi.org/10.3390/life14070797
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11278182_p22
|
PMC11278182
|
sec[2]/sec[4]/p[0]
|
3.5. Change in Carbon Fixation and Central Carbon Metabolism in Response to Urea Addition
| 3.935547 |
biomedical
|
Study
|
[
0.9990234375,
0.0002665519714355469,
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[
0.99951171875,
0.00043010711669921875,
0.00022327899932861328,
0.00004792213439941406
] |
To survey urea addition on the CCM (carbon concentrating mechanism) and photosynthetic carbon fixation in N. oceanica , we first explored transcriptional changes in various pathways, consisting of glycolysis, gluconeogenesis, the carbon concentrating mechanism, and Calvin–Benson cycle .
|
[
"Han Zhu",
"Zhenli Ye",
"Zhengru Xu",
"Li Wei"
] |
https://doi.org/10.3390/life14070797
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11278182_p23
|
PMC11278182
|
sec[2]/sec[4]/p[1]
|
3.5. Change in Carbon Fixation and Central Carbon Metabolism in Response to Urea Addition
| 4.304688 |
biomedical
|
Study
|
[
0.9990234375,
0.00036454200744628906,
0.00037479400634765625
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[
0.99951171875,
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0.0000794529914855957
] |
Firstly, as for CCM, one carbonic anhydrase gene (CA), responsible for the conversion between CO 2 and HCO 3 − , was annotated as a key component of CCM . The significant increases in g2018 by 26.86-fold suggest urea regulates CCM at the RNA level ( Table 3 ). This implies that urea addition enhances carbon-concentrating mechanisms in microalgae, involving organic carbon in the metabolic processes that promote biological growth. Similar conclusions were drawn in Microcystis aeruginosa . Unfortunately, we did not annotate candidate genes responsible for bicarbonate transport, another crucial component of CCM. However, other transporters that may be involved in bicarbonate transport change under nitrogen deficiency conditions and change further under urea conditions . The bile acid: sodium cotransporter (BASS) is thought to mediate the entry of acetoacetic acid into the peroxisome. After nitrogen deficiency, transcription levels of BASS gradually increased . Although no differential expression of BASS was detected, the sodium/hydrogen exchange family protein ( Table 3 ), which is responsible for maintaining the equilibrium of sodium ion inflow, was found to be downregulated by a fold change of 2.64. In addition, we observed upregulated expression of the ATP/ADP transporter ( Table 3 ).
|
[
"Han Zhu",
"Zhenli Ye",
"Zhengru Xu",
"Li Wei"
] |
https://doi.org/10.3390/life14070797
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11278182_p24
|
PMC11278182
|
sec[2]/sec[4]/p[2]
|
3.5. Change in Carbon Fixation and Central Carbon Metabolism in Response to Urea Addition
| 4.25 |
biomedical
|
Study
|
[
0.9990234375,
0.0003561973571777344,
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[
0.99951171875,
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] |
Secondly, in terms of photosynthetic carbon sequestration, we pay special attention to genes participating in the Calvin cycle. Those genes were observed, including PGK (phosphoglycerate kinase), GPDH (glyceraldehyde-3-phosphate dehydrogenase), RPE (ribulose-phosphate 3-epimerase), and TL (transketolase), showed varying degrees of upregulation . This suggests increased carbon fixation in microalgae, leading to the accumulation of carbon compounds. This signifies the strengthening of the Calvin cycle. The upregulation of genes related to the electron transport chain, associated with the degradation of photosynthetic pigments, combined with urea addition, suggests compensation for the energy consumption caused by pigment degradation, enhancing the Calvin cycle and promoting the carbon fixation capacity of microalgae. Based on physiological measurement results, the total amount of carbohydrates in the experimental group was higher than that in the control group, providing some support for this inference . The key product of the Calvin cycle, glyceraldehyde-3-phosphate (G3P), is transformed into pyruvate through the glycolytic pathway, serving as a precursor in lipid biosynthesis .
|
[
"Han Zhu",
"Zhenli Ye",
"Zhengru Xu",
"Li Wei"
] |
https://doi.org/10.3390/life14070797
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11278182_p25
|
PMC11278182
|
sec[2]/sec[4]/p[3]
|
3.5. Change in Carbon Fixation and Central Carbon Metabolism in Response to Urea Addition
| 4.398438 |
biomedical
|
Study
|
[
0.99951171875,
0.0003821849822998047,
0.0002918243408203125
] |
[
0.9990234375,
0.0003674030303955078,
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] |
Thirdly, several genes related to the glycolytic pathway also have different expressions. The downregulation of fructose-1,6-bisphosphate aldolase by 3.02-fold indicates reduced glycolytic activity, emphasizing the accumulation of organic compounds in N. oceanica . In the transcriptome analysis of glycolysis, ALDO (aldolase) showed significant downregulation, while TPI (triose phosphate isomerase) and PGK exhibited significant upregulation . Aldolase plays a crucial role in catalyzing the fourth step of glycolysis, breaking down fructose-1,6-bisphosphate into dihydroxyacetone phosphate (DHAP) and glyceraldehyde-3-phosphate (G3P). TPI facilitates the interconversion between DHAP and G3P, while PGK catalyzes the mutual conversion of 1,3-bisphosphoglycerate and G3P. The differential expression of these three important genes leads to the enrichment of DHAP, providing enhanced energy supply and serving as a key precursor in lipid synthesis, particularly for triacylglycerols (TAGs). Additionally, DHAP participates in lipid degradation through fatty acid beta-oxidation .
|
[
"Han Zhu",
"Zhenli Ye",
"Zhengru Xu",
"Li Wei"
] |
https://doi.org/10.3390/life14070797
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11278182_p26
|
PMC11278182
|
sec[2]/sec[4]/p[4]
|
3.5. Change in Carbon Fixation and Central Carbon Metabolism in Response to Urea Addition
| 4.320313 |
biomedical
|
Study
|
[
0.99951171875,
0.0003325939178466797,
0.0002536773681640625
] |
[
0.99951171875,
0.00030231475830078125,
0.0003306865692138672,
0.00009077787399291992
] |
Fourthly, in the tricarboxylic acid cycle (TCA), the transcription levels of SDH , FHD , and MDH were upregulated by two-fold , indicating the enhancement of the TCA cycle as a central hub for carbohydrate, lipid, and protein metabolism. On the one hand, it provides an energy supply, and on the other hand, it facilitates the transfer of carbon and nitrogen in response to urea addition. Acetyl-CoA can directly supply the TCA cycle or undergo a bypass process in citrate synthesis using aconitase . Nitrogen concentration and the presence of organic C guide metabolism toward lipid or carbohydrate production . This indicates that microalgae have adjusted their metabolic strategies. We observed the expression of malate dehydrogenase ( MDH ) in the experimental group, while its FPKM value was 0 in the control group. MDH catalyzes the oxidation of citrate to oxaloacetate, and the produced NADH further contributes to the generation of ATP from ADP, serving as a major source of cellular energy.
|
[
"Han Zhu",
"Zhenli Ye",
"Zhengru Xu",
"Li Wei"
] |
https://doi.org/10.3390/life14070797
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999995 |
PMC11278182_p27
|
PMC11278182
|
sec[2]/sec[4]/p[5]
|
3.5. Change in Carbon Fixation and Central Carbon Metabolism in Response to Urea Addition
| 4.386719 |
biomedical
|
Study
|
[
0.9990234375,
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[
0.9990234375,
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Lastly, in the transcriptome analysis of the C4 cycle pathway, only one malic acid dehydrogenase was found ( Table 3 ), catalyzing the oxidation of malic acid to oxaloacetate, reducing NAD + to NADH in a reversible reaction. As this enzyme does not participate in CO 2 fixation, it is more likely involved in supplementing intermediates of the TCA cycle to lipid biosynthesis rather than redirecting CO 2 to the plastid for carbon fixation. Acetyl-CoA can also be produced from pyruvate through the “pyruvate dehydrogenase bypass” process, where pyruvate decarboxylase (PDC) and aldehyde dehydrogenase (ALDH) converts pyruvate to acetyl acetate. Although PDC was not detected, two ALDH enzymes were found . The transcription level of g2887 was upregulated by 2.71-fold, while g956 was downregulated by 2.36-fold. One of the ALDH enzymes is located in the cytoplasm, suggesting its involvement in converting cytoplasmic pyruvate (possibly from glycolysis) to acetyl acetate. Acetyl acetate is generated in the cytoplasm through the PDHC pathway and in the mitochondria then forms flexible acetyl-CoA through acetyl-CoA synthetase. These changes may represent a cellular adjustment to energy balance in response to the new growth conditions (urea addition).
|
[
"Han Zhu",
"Zhenli Ye",
"Zhengru Xu",
"Li Wei"
] |
https://doi.org/10.3390/life14070797
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11278182_p28
|
PMC11278182
|
sec[2]/sec[5]/p[0]
|
3.6. Lipid Metabolism Affected by Urea Addition
| 4.15625 |
biomedical
|
Study
|
[
0.99951171875,
0.0002930164337158203,
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] |
[
0.99951171875,
0.00019824504852294922,
0.00015592575073242188,
0.000055730342864990234
] |
To investigate the effect of urea addition in N. oceanica , our study focused on examining how it influences the fatty acid biosynthetic pathway and the synthesis of triacylglycerol (TAG) in N. oceanica . We observed a significant downregulation (2.26-fold) of acetyl-CoA carboxylase ( ACC ) transcript abundance . ACC is a crucial enzyme in the first step of fatty acid biosynthesis. Its main function is to convert acetyl-CoA into malonyl-CoA, a key precursor required for fatty acid synthesis. The downregulation of ACC results in reduced availability of malonyl-CoA, leading to a decrease in the rate of fatty acid synthesis . Other genes related to fatty acid biosynthesis have not been found in the transcriptome or are not differentially expressed.
|
[
"Han Zhu",
"Zhenli Ye",
"Zhengru Xu",
"Li Wei"
] |
https://doi.org/10.3390/life14070797
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11278182_p29
|
PMC11278182
|
sec[2]/sec[5]/p[1]
|
3.6. Lipid Metabolism Affected by Urea Addition
| 4.628906 |
biomedical
|
Study
|
[
0.9990234375,
0.0004982948303222656,
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] |
[
0.99853515625,
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0.00016295909881591797
] |
For TAG (triacylglycerol), first of all, the synthesis process of TAG involves several enzymatic steps. Glycerol-3-phosphate acyltransferase (GPAT) is the enzyme responsible for the first step in TAG synthesis. It catalyzes the formation of glycerol-3-phosphate fatty acid esters by combining glycerol-3-phosphate and fatty acids. The second step of TAG synthesis is the conversion of glycerol-3-phosphate fatty acid ester into lysophosphatidic acid (LPA), the precursor of TAG, catalyzed by lysophosphatidic acid acyltransferase (LPAAT). Fatty acid synthase (FAS) plays an important role in TAG synthesis of long-chain fatty acids. Fatty acid desaturase is involved in the desaturation of fatty acids by introducing double bonds into the fatty acid chain. However, no differential expression of GPAT , LPAAT , or FAS was found. Nevertheless, the transcriptome analysis revealed the presence of the alpha/beta hydrolase fold protein (g20) ( Dataset S1 ). This protein not only participates in the esterification process of fatty acids but also catalyzes the combination of fatty acids and glycerol to form triglycerides (TAG). Moreover, these proteins also exhibit lipid-soluble activity, breaking down lipid molecules (including TAG) into glycerol and fatty acids. The upregulation of g20 in mRNA expression by 2.40-fold suggests an increased expression of these alpha/beta hydrolase fold proteins under the study conditions. This upregulation may indicate enhanced TAG synthesis and lipolytic activity, potentially influencing energy generation and other metabolic pathways . In addition, we found that many other genes for unsaturated fatty acid enzymes are very active. The gene Patatin-like phospholipase, putative exhibited a significant upregulation, with its expression level increasing by 3.65-fold ( Dataset S1 ). Similarly, the gene hydrolase, alpha/beta fold family protein also showed an upregulation, with its expression level increasing by 2.42-fold ( Dataset S1 ). The putative delta-5 fatty acid desaturase and delta-4 fatty acid desaturase both exhibit a significant upregulation of over three-fold ( Dataset S1 ). These enzymes are responsible for introducing double bonds by desaturating the saturated carbon chains in fatty acid molecules. This desaturation process contributes to the synthesis of long-chain fatty acids. The downregulation of Alpha/beta hydrolase by 2.30-fold suggests a potential inhibition of lipid hydrolysis reactions ( Dataset S1 ). This downregulation could lead to the accumulation of lipids within the system. The common end products of de novo FA biosynthesis are C16:0, C18:0, and C18:1 in the plastids of algae and vascular plants .
|
[
"Han Zhu",
"Zhenli Ye",
"Zhengru Xu",
"Li Wei"
] |
https://doi.org/10.3390/life14070797
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11278182_p30
|
PMC11278182
|
sec[2]/sec[5]/p[2]
|
3.6. Lipid Metabolism Affected by Urea Addition
| 4.355469 |
biomedical
|
Study
|
[
0.99951171875,
0.0003192424774169922,
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] |
[
0.9990234375,
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On the other hand, the metabolic performance of fatty acids is also very important. Transcriptome analysis showed that the enzymes involved in β-oxidation were significantly upregulated. Beta-oxidation (β-oxidation) typically occurs in the mitochondria and is utilized to break down fatty acids to generate energy rapidly. It gradually breaks down long-chain fatty acids into shorter acyl-CoA molecules while simultaneously producing abundant ATP energy. Transcriptome analysis indicates that Acyl-CoA dehydrogenase and Acyl-CoA oxidase were upregulated by 3.76- and 2.30-fold, respectively ( Dataset S1 ). These enzymes play crucial roles in fatty acid metabolism and are involved in various biochemical processes within the cell. Acyl-CoA dehydrogenase is responsible for catalyzing the alpha, and beta-dehydrogenation of acyl-CoA molecules, a key step in fatty acid degradation. On the other hand, Acyl-CoA oxidase is involved in the oxidation of acyl-CoA molecules. The upregulation of these enzyme genes suggests an increased demand for fatty acid metabolism or energy production in the analyzed context. These enzymes are essential for breaking down fatty acids, which can be used as an energy source or as building blocks for various cellular processes . The upregulation of genes encoded Acyl-CoA dehydrogenase and Acyl-CoA oxidase indicates an enhanced capacity for fatty acid utilization and suggests an active metabolic state in the studied system.
|
[
"Han Zhu",
"Zhenli Ye",
"Zhengru Xu",
"Li Wei"
] |
https://doi.org/10.3390/life14070797
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11278182_p31
|
PMC11278182
|
sec[2]/sec[5]/p[3]
|
3.6. Lipid Metabolism Affected by Urea Addition
| 4.226563 |
biomedical
|
Study
|
[
0.9990234375,
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[
0.99951171875,
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] |
In comparison with other algae studies, it can be found that the response strategies adopted by N. oceanica are different. In the presence of urea, diatoms tend to exhibit higher lipid synthesis activity. The lipid metabolism strategy of diatoms may favor carbon storage . On the other hand, green algae, in urea conditions, tend to show lower lipid synthesis activity. Green algae may prioritize nitrogen utilization to support growth and protein synthesis . This suggests that green algae may focus more on nitrogen uptake and metabolism rather than lipid accumulation. Based on the measured total lipid content comparison, the experimental group and the control group showed no significant differences, which supports this viewpoint to some extent . Through the analysis of metabolic pathways, it is evident that the proportion of mRNA expression related to unsaturated fatty acids significantly increases. This indicates that under the addition of urea, N. oceanica enhances the rate of synthesizing unsaturated fatty acids to adapt to environmental changes. Overall, the addition of urea enhances lipid metabolism. Urea metabolism releases bicarbonate ions (HCO 3 − ), further promoting the growth and lipid metabolism of N. oceanica . Additionally, there are alterations in the composition of lipid production in N. oceanica .
|
[
"Han Zhu",
"Zhenli Ye",
"Zhengru Xu",
"Li Wei"
] |
https://doi.org/10.3390/life14070797
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11278182_p32
|
PMC11278182
|
sec[2]/sec[6]/p[0]
|
3.7. Folate Metabolism Affected by Urea Addition
| 4.691406 |
biomedical
|
Study
|
[
0.9990234375,
0.0007538795471191406,
0.0003840923309326172
] |
[
0.998046875,
0.0007114410400390625,
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0.00030422210693359375
] |
Interestingly, we note a significant activity in the derivative folate metabolism. Folate serves as the predominant supplier and receptor of one-carbon units in the majority of organisms, playing a vital role in various essential metabolic processes such as methylation cycles, amino acid metabolism, and the biosynthesis of nucleotides . The first stage of folate metabolism is commonly facilitated by dihydrofolate reductase , employing NADPH as a coenzyme to enzymatically reduce folate to dihydrofolate. Subsequently, DHFR further reduces dihydrofolate to tetrahydrofolic acid . Methylenetetrahydrofolate reductase exhibited a 2.03-fold upregulation at the mRNA level . This enzyme, a key regulator in the methyl cycle, catalyzes the conversion of 5,10-methylenetetrahydrofolate (5,10-MTHF) to 5-methyltetrahydrofolate (5-MTHF). It plays a crucial role in folate metabolism, DNA synthesis, and methylation reactions . Adenosylhomocysteinase and Methylthioadenosine/S-Adenosylhomocysteine nucleosidase (g648) catalyzes the reversible hydrolysis of S-Adenosylhomocysteine (SAH), breaking it down into adenosine and homocysteine. At the mRNA level, both showed a significant upregulation (5.56-fold and 2.29-fold, respectively) . Homocysteine undergoes two metabolic pathways in the body. Firstly, it can be converted into methionine through a remethylation process, involving a key gene for methionine synthesis. Notably, the formation of methionine is associated with remethylation, but the specific gene responsible for the synthesis of methionine has not been detected. Secondly, homocysteine enters the transsulfuration pathway, where it combines with serine catalyzed by cystathionine beta-synthase and its cofactor vitamin B6 (not yet identified) ( Dataset S1 ). This interaction leads to a two-step reaction resulting in the formation of cysteine and α-ketobutyric acid. Seipiapterin Reductase , an essential enzyme in folate resynthesis, is downregulated by 2.79-fold at the transcriptional level under Ct vs. U ( Dataset S1 ). Folate metabolism likely acts as a pivotal hub, contributing to the redistribution of carbon and nitrogen. On one hand, it plays a role in amino acid synthesis (such as methionine), protein synthesis, DNA methylation, and other biological processes. On the other hand, it may impact gene expression by participating in de novo synthesis of purines and pyrimidines .
|
[
"Han Zhu",
"Zhenli Ye",
"Zhengru Xu",
"Li Wei"
] |
https://doi.org/10.3390/life14070797
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11278182_p33
|
PMC11278182
|
sec[3]/p[0]
|
4. Conclusions
| 4.152344 |
biomedical
|
Study
|
[
0.99951171875,
0.0002963542938232422,
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] |
[
0.99951171875,
0.00014853477478027344,
0.00025153160095214844,
0.00005829334259033203
] |
Using the mRNA-Seq, we systematically investigated the response of N. oceanica to the addition of urea. This study provides novel insights into the regulation mechanism in response to urea addition. Over a 14-day growth period, there was no significant difference in cell concentration in the experimental group compared to the control group. However, at the transcriptional level, N. oceanica actively and dynamically regulates the redistribution of carbon and nitrogen after urea addition. To acclimate to urea addition, photosynthesis, carbon/nitrogen metabolism, fatty acid biosynthesis, and lipid metabolism were reprogrammed. Those processes such as amino acid and protein synthesis and degradation, as well as carbon fixation, are enhanced under urea addition. Notably, genes associated with lipases or polyunsaturated fatty acid enzymes were highly activated. These data will serve as a reference for future in-depth research into the effects of urea on N. oceanica .
|
[
"Han Zhu",
"Zhenli Ye",
"Zhengru Xu",
"Li Wei"
] |
https://doi.org/10.3390/life14070797
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999995 |
PMC11278194_p0
|
PMC11278194
|
sec[0]/p[0]
|
1. Introduction
| 3.923828 |
biomedical
|
Review
|
[
0.9970703125,
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[
0.01380157470703125,
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] |
Erectile dysfunction (ED) is defined as the inability to attain or maintain a rigid erection for satisfactory intercourse. It is a medical condition that affects countless males and is particularly awkward in those who are young and actively engaged in sexual activity . Unsurprisingly, many studies of interest have been conducted and reviewed . A lot of attention has been paid to married life in this context as exemplified by the studies produced during the COVID-19 pandemic . Normal penile erection is the result of an interplay between healthy hormonal, arterial, neurological, pharmacological, systemic metabolic, psychological factors and the corpora cavernosa remaining free from cavernosal fibrosis . Consequently, ED can occur if any of the said contributors is unhealthy .
|
[
"Ko-Shih Chang",
"Cho-Hsing Chung",
"Yi-Kai Chang",
"Geng-Long Hsu",
"Mang-Hung Tsai",
"Jeff SC Chueh"
] |
https://doi.org/10.3390/life14070911
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11278194_p1
|
PMC11278194
|
sec[0]/p[1]
|
1. Introduction
| 4.128906 |
biomedical
|
Review
|
[
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[
0.00634002685546875,
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0.990234375,
0.0006589889526367188
] |
Regarding ED treatment strategies, the discovery of phosphodiesterase type 5 (PDE-5) inhibitors, e.g., Sildenafil, opened the door for medical treatment , with this agent becoming the main ED treatment option Would the inventor translate the sagacious words” opportunity favors prepared mind”? . However, there are many ED treatment strategies because of the paucity of ED panacea, with at least 30% of ED patients not responding to this group of agents. This number is particularly high in young males suffering from veno-occlusive dysfunction (VOD) . Even though VOD is the most prevalent contributor to the ED pathophysiology, including in those whose ED results from heavy smoking , patients with VOD are typically administered oral vasodilators first and later offered second-line treatment strategies, including vacuum constriction devices, injection vasodilator therapy, endovascular therapies, or penile implantation . Recently, there has been practical developments in the field of low-energy shock-wave therapy (ESWT) for ED , which, much like PDE-5 inhibitors before, has become extremely popular. Despite this, penile implants remain the most reliable solution among the ED treatment options listed , though serious complications, e.g., mechanical failure, infection, and prosthesis extrusion, still sometimes occur .
|
[
"Ko-Shih Chang",
"Cho-Hsing Chung",
"Yi-Kai Chang",
"Geng-Long Hsu",
"Mang-Hung Tsai",
"Jeff SC Chueh"
] |
https://doi.org/10.3390/life14070911
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999999 |
PMC11278194_p2
|
PMC11278194
|
sec[0]/p[2]
|
1. Introduction
| 4.066406 |
biomedical
|
Study
|
[
0.966796875,
0.032958984375,
0.0002143383026123047
] |
[
0.8037109375,
0.04632568359375,
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0.09735107421875
] |
Penile vascular interventions aim to treat VOD or arterial insufficiency by limiting blood outflow or increasing arterial inflow in the penis . Many physicians and researchers are continually seeking improvements in these procedures. To this end, pudendal stents and penile venous embolization have been introduced to treat VOD and arterial insufficiency . Coil embolization (CE) has also returned as an option in the last decades. It is claimed to be an effective strategy with minimally invasive options owing to its simplicity and reproducibility . Conspicuously, penile venous stripping (PVS) developed in 1986 , after a refined penile venous stripping treatment method won a USPTO patent on 14 August 2012 , many refractory young patients with VOD began requesting PVS. To fill the research gap, herein, we report five young patients who underwent penile venous CE, supplemented with a narrative literature review of CE as a treatment for VOD and varicocele.
|
[
"Ko-Shih Chang",
"Cho-Hsing Chung",
"Yi-Kai Chang",
"Geng-Long Hsu",
"Mang-Hung Tsai",
"Jeff SC Chueh"
] |
https://doi.org/10.3390/life14070911
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999999 |
PMC11278194_p3
|
PMC11278194
|
sec[1]/p[0]
|
2. Methods
| 3.777344 |
biomedical
|
Study
|
[
0.99072265625,
0.0089874267578125,
0.00018286705017089844
] |
[
0.98095703125,
0.005859375,
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] |
We conducted this retrospective study with case reports and a literature review after it was approved by the institutional review board of China Medical University (CMUH112-REC1-077) on 3 May 2023. This article details five men who received CE and is supplemented by a narrative literature review. Journals in andrology, urology, radiology, and medicine-related fields were examined using MEDLINE. The search used the following terms in various combinations: erectile dysfunction, coil embolization for treating patients with erectile dysfunction, conspicuously veno-occlusive dysfunction, an older venous leak, and varicocele testis.
|
[
"Ko-Shih Chang",
"Cho-Hsing Chung",
"Yi-Kai Chang",
"Geng-Long Hsu",
"Mang-Hung Tsai",
"Jeff SC Chueh"
] |
https://doi.org/10.3390/life14070911
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11278194_p4
|
PMC11278194
|
sec[1]/sec[0]/p[0]
|
Case Series of Five Patients
| 3.720703 |
clinical
|
Clinical case
|
[
0.1612548828125,
0.83447265625,
0.00406646728515625
] |
[
0.004795074462890625,
0.007556915283203125,
0.0025844573974609375,
0.98486328125
] |
Case 1 : A 33-year-old male dentist, born in 1979, had been suffering from very early detumescence since adolescence. He was impatient to wait for other options and resorted to penile implantation to treat his ED. Thus, he underwent penile venous coil embolization (CE) to treat veno-occlusive dysfunction (VOD) due to a long-term venous leak in 2011. Unfortunately, after the coil implant, the early detumescence remained the same and poorer erection rigidity ensued; he was referred for our medical assistance in 2012. A dual pharmaco-cavernosography scout film demonstrated several dozen coils lodged within the periprostatic venous plexus , and VOD was confirmed in a corresponding pharmaco-cavernosography . The coils remained in situ at the patient’s last evaluation .
|
[
"Ko-Shih Chang",
"Cho-Hsing Chung",
"Yi-Kai Chang",
"Geng-Long Hsu",
"Mang-Hung Tsai",
"Jeff SC Chueh"
] |
https://doi.org/10.3390/life14070911
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999995 |
PMC11278194_p5
|
PMC11278194
|
sec[1]/sec[0]/p[1]
|
Case Series of Five Patients
| 3.230469 |
clinical
|
Clinical case
|
[
0.179443359375,
0.814453125,
0.00600433349609375
] |
[
0.003047943115234375,
0.0070037841796875,
0.0017604827880859375,
0.98828125
] |
Case 2 : A 42-year-old housebuilder, born in 1972, had suffered from ED resulting from VOD since 1994 and received penile venous CE in 2000. He experienced some improvement in erection quality from 2000 to 2003, but then ED recurred, with a subsequent physician declining his request for CE in 2005. Refractory ED prompted him to seek out medical assistance for which he traveled over 10,000 km in November 2014. Pharmarco-cavernosography demonstrated significant VOD. Surprisingly, although a pelvic X-ray failed to find coil imaging, a chest X-ray disclosed five coils lodged in pulmonary arteries .
|
[
"Ko-Shih Chang",
"Cho-Hsing Chung",
"Yi-Kai Chang",
"Geng-Long Hsu",
"Mang-Hung Tsai",
"Jeff SC Chueh"
] |
https://doi.org/10.3390/life14070911
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11278194_p6
|
PMC11278194
|
sec[1]/sec[0]/p[2]
|
Case Series of Five Patients
| 3.683594 |
clinical
|
Clinical case
|
[
0.06585693359375,
0.9306640625,
0.0033626556396484375
] |
[
0.00600433349609375,
0.00811767578125,
0.0026798248291015625,
0.9833984375
] |
A contrast CT scan confirmed two coils installed in the left and right pulmonary arterial trees. The coils were tightly adhesive to the vessel wall; a coil had traversed the right ventricle wall and lodged within the pericardium . He received PVS of the excessive drainage veins with an uneventful postoperative course. He experienced a significant improvement parallel to a postoperative cavernosogram with enhanced intracorporeal retention, although it was not entirely satisfactory. Then, a revisit was decided upon to salvage the PVS in April 2016. A chest X-ray and spiral CT demonstrated further migration and perforation of the right ventricle wall and diaphragm by the coil . The liver border was irregular and penetrated, and cirrhosis was incidentally noted. He eventually benefited somewhat from our ambulatory surgery, although our primary concern was morbidity from the uncontrolled coil.
|
[
"Ko-Shih Chang",
"Cho-Hsing Chung",
"Yi-Kai Chang",
"Geng-Long Hsu",
"Mang-Hung Tsai",
"Jeff SC Chueh"
] |
https://doi.org/10.3390/life14070911
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999999 |
PMC11278194_p7
|
PMC11278194
|
sec[1]/sec[0]/p[3]
|
Case Series of Five Patients
| 3.949219 |
clinical
|
Clinical case
|
[
0.10028076171875,
0.8955078125,
0.00431060791015625
] |
[
0.0061187744140625,
0.007232666015625,
0.00408172607421875,
0.982421875
] |
Case 3 : A 31-year-old banker, born in 1985, had suffered from ED resulting from VOD since age 23. He then underwent his first penile venous CE in the northern hemisphere in 2010, with no improvement in erectile function. Table 1 summarizes three CE courses at different medical school-affiliated hospitals. Acute chest pain led him to the emergency room. From an imaging study, he was told that a dumbbell-shaped coil complex was evident in the right pulmonary artery eight days postoperatively. Refractory ED prompted him to receive second and third penile venous CE procedures in 2012 and 2014 at different medical schools. Tapeworm-shaped and pigtail-shaped coils were demonstrated . His ED did not improve. Refractory ED prompted him to seek out medical assistance after a long trip in August 2016. A chest X-ray confirmed a twisted coil complex lodged in the right pulmonary artery, although this patient had experienced no more chest pain since the painful episode in 2010. An abdominal x-ray showed two coils at 90-degree to the body axis: one lodged in the bifurcation region of the left iliac region and the other installed in the right internal pudendal vein level , which corresponded to the coils inserted in 2012 and 2014, respectively. Dual pharmaco-cavernosography showed that the coils did not fit within the internal iliac or pudendal veins regardless of VOD . He had an uneventful course after PVS, which caused significant intracorporeal retention, conspicuously in the penile crura , and flew home on the third postoperative day. Erectile functional improvement is ongoing, and he has resumed sexual activity.
|
[
"Ko-Shih Chang",
"Cho-Hsing Chung",
"Yi-Kai Chang",
"Geng-Long Hsu",
"Mang-Hung Tsai",
"Jeff SC Chueh"
] |
https://doi.org/10.3390/life14070911
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11278194_p8
|
PMC11278194
|
sec[1]/sec[0]/p[4]
|
Case Series of Five Patients
| 3.244141 |
clinical
|
Clinical case
|
[
0.124267578125,
0.87060546875,
0.00531005859375
] |
[
0.0029239654541015625,
0.005649566650390625,
0.0019197463989257812,
0.98974609375
] |
Case 4 and 5: Two university students, born in 1992 and 1993, respectively, had suffered from ED resulting from VOD since the ages of 23 and 21. They underwent their first penile venous CE in the northern hemisphere in 2015 and 2017 with no improvement in erectile function. In 2017 and 2018, intractable ED prompted them to visit our institute, where many inserted coils were noted in the proximal deep dorsal vein and the superficial dorsal vein . Then, they had an uneventful course after PVS and flew home on the third and fourth postoperative days. Erectile functional improvement was noted, and sexual activity was resumed.
|
[
"Ko-Shih Chang",
"Cho-Hsing Chung",
"Yi-Kai Chang",
"Geng-Long Hsu",
"Mang-Hung Tsai",
"Jeff SC Chueh"
] |
https://doi.org/10.3390/life14070911
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11278194_p9
|
PMC11278194
|
sec[2]/p[0]
|
3. Results
| 4.074219 |
biomedical
|
Study
|
[
0.99853515625,
0.0011739730834960938,
0.00021541118621826172
] |
[
0.9052734375,
0.0015392303466796875,
0.09246826171875,
0.0007863044738769531
] |
Inserted coils were seen inside and outside the cardiovascular circulation system, particularly in the erection-related veins of the de novo penile fibro-vascular assembly to the pulmonary arteries, including the deep dorsal veins (n = 4), periprostatic plexus (n = 5), iliac vein (n = 5), right pulmonary artery (n = 2), left pulmonary artery (n = 2), and right ventricle (n = 1), with cardiac wall perforation being noted within one and half years. The average follow-up period was 6.3 ± 2.1 years. Even though the radiopacity was marginally enhanced after penile venous stripping, certain objective improvements were evidenced in the imaging data and the IIEF-5 score and EHS scale. Regarding publications on coil therapy for treating VOD, six articles recommend it highly, whereas one regards it as an acceptable option. All claim it as minimally invasive and effective. In addition, EC for the treatment of varicocele testis is consistently recommended parallel to brain vasculature treatment.
|
[
"Ko-Shih Chang",
"Cho-Hsing Chung",
"Yi-Kai Chang",
"Geng-Long Hsu",
"Mang-Hung Tsai",
"Jeff SC Chueh"
] |
https://doi.org/10.3390/life14070911
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11278194_p10
|
PMC11278194
|
sec[2]/sec[0]/p[0]
|
Literature Review of Endovascular Coil Embolization
| 4.121094 |
biomedical
|
Review
|
[
0.99072265625,
0.006381988525390625,
0.0030727386474609375
] |
[
0.007373809814453125,
0.040985107421875,
0.94970703125,
0.0017290115356445312
] |
Vascular diseases occur throughout the human body because every organ system requires the nutrition that a functional cardiovascular system supplies . As a rule, the amount of drainage blood should equal the amount supplied to each independent organ. Given that no one can avoid vascular disorders, most men will confront the ED issue in their lives. Like other organs, in the human penis, vascular disorders can be categorized into arterial, venous insufficiency, and a mixed-type disorder. In recent decades, every professional has benefited from advanced technologies and research themes as was exemplified by the COVID-19 vaccine . Similarly, state-of-the-art tools have been widely developed to reduce invasiveness in every subspecialist surgery and the related procedures are, thus, collectively categorized as minimally invasive techniques . Endovascular intervention is one typical example. An embolus could be of natural origin, such as a pathological bolus in the pulmonary embolism, or an artificial device for therapeutic purposes, such as in the hemostatic treatment of idiopathic intractable epistaxis . Another practice is that of blocking a tumor-feeding artery to starve the tumor cells . Overall, surgery has a more versatile role in clinical medicine than ever before and has become the mainstay of interventional radiology practice because of its simplicity and reproducibility .
|
[
"Ko-Shih Chang",
"Cho-Hsing Chung",
"Yi-Kai Chang",
"Geng-Long Hsu",
"Mang-Hung Tsai",
"Jeff SC Chueh"
] |
https://doi.org/10.3390/life14070911
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11278194_p11
|
PMC11278194
|
sec[2]/sec[0]/p[1]
|
Literature Review of Endovascular Coil Embolization
| 4.183594 |
biomedical
|
Review
|
[
0.998046875,
0.0012884140014648438,
0.0007677078247070312
] |
[
0.34912109375,
0.0013914108276367188,
0.6484375,
0.0007681846618652344
] |
Despite endovascular coiling being developed with multidisciplinary collaboration through the synthesis of several innovations between 1970 and 1990 in the field of electronics, neurosurgery, and interventional radiology , it does not appear to be applicable for ED resulting from penile arterial insufficiency that would not benefit from angioplasty or an arterial stent. In addition, we assessed the literature on CE for treating ED resulting from VOD, which is commonly believed to be a minimally invasive effective strategy. Furthermore, we analyzed various representative articles covering coiled embolization for varicocele testis , which is so common that it is used in commonplace issues such as hemorrhoids . To build a comprehensive overview, Table 2 provides a general summary. With a sample size of just 18, Courtheoux published an article on coiled embolization for treating ED resulting from VOD in which embolization treatment success was reported in 15 of 17 (83.3%) patients in 1985 . He later reported that 26 patients benefited from this procedure from a group of 40, with a 65% success rate. He concluded that this technique was simple, safe, and effective in treating impotence caused by venous leakage in 1986 . A similar article was published in a different language in 1987 . In 1991, the sample size was expanded to 46 patients, with a success rate of 57% after eight-month follow-up . However, in 1994, Schild reported a success rate of just 22.2% among 19 patients with a 25-month follow-up . In 1998, Malossini used coil embolization plus partial resection of the proximal venous trunk on 17 patients and noted 11 patients with a successful outcome from 19 males being followed-up . In 2014, Rebonato performed sclerosing embolization on patients who underwent coiled embolization, reporting that 7 males out of 18 benefited in a follow-up period of 13.3 months . Carrino applied sclerosing embolization with the Valsalva maneuver on 171 patients with a 77.2% success rate, with a follow-up for six months ; however, only the abstract is available. The full article would be of considerable interest since the case number is as large as 171. Regarding varicocele, coil embolization appears to be more effective in many publications; here, we analyze a representative article for comparison. In 2009, Bechara reported a success rate of 95% on 41 patients in a follow-up period of 39.3 months . Moreover, Kutlu reported the application of coil embolization in 32 patients with varicocele, although migration occurred . In 2018, Markris published a review article on coil embolization in 898 patients with varicocele with a 90.9% success rate .
|
[
"Ko-Shih Chang",
"Cho-Hsing Chung",
"Yi-Kai Chang",
"Geng-Long Hsu",
"Mang-Hung Tsai",
"Jeff SC Chueh"
] |
https://doi.org/10.3390/life14070911
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11278194_p12
|
PMC11278194
|
sec[2]/sec[0]/p[2]
|
Literature Review of Endovascular Coil Embolization
| 3.953125 |
biomedical
|
Review
|
[
0.99658203125,
0.0023517608642578125,
0.0012912750244140625
] |
[
0.0133819580078125,
0.01548004150390625,
0.97021484375,
0.0007333755493164062
] |
In summary, advanced medicine takes advantage of material science and engineering, leading to advances in clinical applications, as will be the case with artificial intelligence. In this manner, physicians can develop more accessible and effective strategies for confronting human diseases. Therefore, coil embolization deserves to be explored, especially as varicocele and VOD are the most common disease entities in urology. In the medical literature, six articles highly recommend CE for treating VOD and long-term venous leak, claiming to be minimally invasive and effective, but none of these are from the recent decades. In contrast, CE is recommended for treating varicocele, although coil migration to the right heart ventricle can occur.
|
[
"Ko-Shih Chang",
"Cho-Hsing Chung",
"Yi-Kai Chang",
"Geng-Long Hsu",
"Mang-Hung Tsai",
"Jeff SC Chueh"
] |
https://doi.org/10.3390/life14070911
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11278194_p13
|
PMC11278194
|
sec[3]/p[0]
|
4. Discussion
| 4.222656 |
biomedical
|
Study
|
[
0.9931640625,
0.006664276123046875,
0.0002655982971191406
] |
[
0.9384765625,
0.02447509765625,
0.033782958984375,
0.0031986236572265625
] |
Endovascular coiling can be successfully applied to reduce blood circulation to brain aneurysms using microsurgical detachable platinum wires, with the clinician inserting one or more into the aneurysm until it is determined that blood flow is no longer occurring within the space. While the procedure itself has been and continues to be compared to surgical clipping, the development of the concept and procedure has resulted in it becoming a practice in many centers and subspecialist fields . In the human body, many veins, especially those in the legs, penis, and testicular veins, have one-way valves. Each valve consists of two cusps with edges that meet. When blood flow moves toward the heart, it pushes the cusps open like one-way swinging doors. If gravity or muscle contractions try to pull the blood backward or if blood begins to back up in a vein, the cusps are pushed closed, preventing backward flow . As the venous wall can only sustain a low pressure, it is understandable penile erection rigidity can be compromised because all emissary veins communicate freely between the cavernosal sinusoids and periprostatic venous plexus. Thus, the endovascular coiling procedure can establish a environment whereby pressure–vein communication is unrestricted in a corpora cavernosa suffering from VOD. The question is, therefore, how is erection rigidity attainable? In our clinical experience and after assessing six cases of endovascular sclerotherapy, the venous occlusion location is represented by the emissary veins close to the outer tunica, which is an exclusive physiological way to establish the corpora cavernosa (CC) in order to free them from VOD. In addition, the surgical method should aim to cure VOD rather than partially blocking vessels far from the CC chamber as a result of CE. Thus, endovascular interventions for treating VOD warrants further scientific study in the future.
|
[
"Ko-Shih Chang",
"Cho-Hsing Chung",
"Yi-Kai Chang",
"Geng-Long Hsu",
"Mang-Hung Tsai",
"Jeff SC Chueh"
] |
https://doi.org/10.3390/life14070911
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11278194_p14
|
PMC11278194
|
sec[3]/p[1]
|
4. Discussion
| 4.046875 |
biomedical
|
Study
|
[
0.8984375,
0.10113525390625,
0.00046133995056152344
] |
[
0.6025390625,
0.074951171875,
0.1112060546875,
0.211181640625
] |
In the literature review, endovascular coiling was shown to be appropriate for treating varicocele testis because the blood flow does not vary much based on physiological requirements. Astonishingly, a migration of the coil in the right ventricle was reported . Despite the large patient population having undergone endovascular coiling for varicocele testis and the rate of coil migration being so rare, this extreme complication does occur and deserves to be monitored. In contrast, despite the small patient population having undergone endovascular coiling for VOD issues, uncontrolled coil migration to the pulmonary artery was reported as early as 1993 . We were consulted by six patients who underwent endovascular coiling to treat VOD from 2012 to 2017, with five of them visiting our institute in person six times. In these patients, not only did endovascular coiling have little benefit for their ED issues, but extraordinary complications also occurred, such as coil migration along the pulmonary artery tree and into the lower right pulmonary artery within one week, coil migration into the right ventricle within five years, and further cardiac wall penetration in one and half years thereafter . We believe that potential patients should be informed about these risks as the heart and cardiovascular system are involved. Although we are unaware of a method of avoiding coil migration, we feel the sharpness of the coil edge may have contributed to its migration out of the vessel in the case of the 31-year-old banker.
|
[
"Ko-Shih Chang",
"Cho-Hsing Chung",
"Yi-Kai Chang",
"Geng-Long Hsu",
"Mang-Hung Tsai",
"Jeff SC Chueh"
] |
https://doi.org/10.3390/life14070911
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11278194_p15
|
PMC11278194
|
sec[3]/p[2]
|
4. Discussion
| 4.140625 |
biomedical
|
Study
|
[
0.998046875,
0.0016527175903320312,
0.00015938282012939453
] |
[
0.86669921875,
0.0243377685546875,
0.10540771484375,
0.0037631988525390625
] |
Endovascular coiling may be an easy treatment option for physicians confronted with a patient with VOD owing to its simplicity, reproducibility, and low morbidity. Moreover, it is effective and safe in various vascular diseases and would be a positive option if functional for VOD treatment. Among venous treatment options, penile venous embolization is an old method that is now being newly assessed from the perspective of interventional radiology. It appears safe, although the surprising morbidity of the 42-year-old house builder and 31-year-old banker described herein underscores the need for caution . Human erectile rigidity only occurs if the corpora cavernosa is healthy (CC). The CC sinusoids are encircled by the bi-layered tunica albuginea, which is essential in the erection mechanism. On full erection, CC arterial inflow increases from 2–3 mL/min to 60–80 mL/min, which is the same in the CC suffering from VOD. This implies that a penile venous embolization coil is at risk of migrating throughout the body once it is inserted in the main common drainage channel of the CC.
|
[
"Ko-Shih Chang",
"Cho-Hsing Chung",
"Yi-Kai Chang",
"Geng-Long Hsu",
"Mang-Hung Tsai",
"Jeff SC Chueh"
] |
https://doi.org/10.3390/life14070911
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11278194_p16
|
PMC11278194
|
sec[3]/p[3]
|
4. Discussion
| 4.269531 |
biomedical
|
Study
|
[
0.99853515625,
0.0011224746704101562,
0.0001232624053955078
] |
[
0.99365234375,
0.0011911392211914062,
0.004909515380859375,
0.0004801750183105469
] |
Recent research described the penile fibro-vascular assembly as a new frontier of the human cardiovascular system . The penile venous anatomy includes one deep dorsal vein, two cavernosal veins, and two pairs of para-arterial veins (as opposed to one single vein), all situated between Buck’s fascia and tunica. These erection-related veins are the principal components in erectile rigidity and drain the sinusoidal blood out of the corpora cavernosa, before becoming confluent to the periprostatic venous plexus. Moreover, large patient populations seek and benefit from anatomy-based penile venous stripping surgery for ED resulting from veno-occlusive dysfunction. The ideal solution for treating penile veno-occlusive dysfunction should limit blood flow close to the tunic outer longitudinal layer, where the veno-occlusive mechanism operates . This implies that an effective strategy for treating penile erection-related veins should aim at the level closest to the more extended longitudinal tunica albuginea layer. Accordingly, the efficacy of venous embolization warrants further research because it only treats the vascular channels outside the corpora cavernosa, which may be why penile venous embolization is ineffective, as evidenced in this five-patient case series.
|
[
"Ko-Shih Chang",
"Cho-Hsing Chung",
"Yi-Kai Chang",
"Geng-Long Hsu",
"Mang-Hung Tsai",
"Jeff SC Chueh"
] |
https://doi.org/10.3390/life14070911
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11278194_p17
|
PMC11278194
|
sec[4]/p[0]
|
5. Conclusions
| 3.716797 |
biomedical
|
Study
|
[
0.99853515625,
0.0010900497436523438,
0.0001800060272216797
] |
[
0.998046875,
0.0014543533325195312,
0.00038313865661621094,
0.0003387928009033203
] |
In summary, we found that migrating coils can flow through the cardiovascular systemic circulation until they encounter an impedance. Thus, penile endovascular coiling may incur the risk of extreme complications, including cardiac wall penetration, and patients should be informed of this possibility before choosing coil embolization to treat ED resulting from VOD. Our study has certain limitations, including the small sample size (five patients) and its retrospective nature.
|
[
"Ko-Shih Chang",
"Cho-Hsing Chung",
"Yi-Kai Chang",
"Geng-Long Hsu",
"Mang-Hung Tsai",
"Jeff SC Chueh"
] |
https://doi.org/10.3390/life14070911
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11278206_p0
|
PMC11278206
|
sec[0]/p[0]
|
1. Introduction
| 4.042969 |
biomedical
|
Review
|
[
0.99853515625,
0.0010232925415039062,
0.0005331039428710938
] |
[
0.16015625,
0.01436614990234375,
0.82470703125,
0.0008177757263183594
] |
Over the past twenty years, the Food and Drug Administration (FDA) has approved a minimum of 20 new molecular entities that target oncogenic driver mutations in non-small cell lung cancer (NSCLC) . These targeted therapies have led to some NSCLC studies reporting a median overall survival (OS) over three years in the metastatic setting . While more than fifty percent of non-squamous NSCLC patients may have a mutation with an FDA-approved therapy, there remains a distinct unmet medical need for those with epigenetic dysregulation that may be more challenging to target . This need is particularly vital given that the five-year survival rate for Stage IV NSCLC patients in 2020 was only 8.2% .
|
[
"Peter Manolakos",
"Luigi Boccuto",
"Diana S. Ivankovic"
] |
https://doi.org/10.3390/jpm14070684
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11278206_p1
|
PMC11278206
|
sec[0]/p[1]
|
1. Introduction
| 4.160156 |
biomedical
|
Review
|
[
0.99267578125,
0.004634857177734375,
0.0026092529296875
] |
[
0.010467529296875,
0.001262664794921875,
0.98779296875,
0.0006985664367675781
] |
This critical review analyzes the current literature on the impact of mutations in the SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily A, member 4 ( SMARCA4 ) gene, focusing on the survival outcomes for patients with NSCLC. Typically, patients with SMARCA4 -deficient NSCLC clinically present with adenocarcinoma, larger invasive tumor size, a smoking history, and fewer epidermal growth factor receptor (EGFR) mutations ( p < 0.05) . In addition, SMARCA4 -mutated NSCLCs are associated with a higher likelihood of negative or low programmed cell death ligand-1 (PD-L1) expression ( p =0.03) and higher tumor mutational burden (TMB) as compared to wild-type (WT) cases ( p < 0.001) .
|
[
"Peter Manolakos",
"Luigi Boccuto",
"Diana S. Ivankovic"
] |
https://doi.org/10.3390/jpm14070684
|
N/A
|
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en
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1. Introduction
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biomedical
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Study
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SMARCA4 mutations occur in approximately 5–7% of all human cancers and 7–11% of NSCLC cases . Two classes of SMARCA4 alterations are linked to epigenetic dysregulation . Class 1 mutations encompass truncating mutations, fusions, and homozygous deletions, typically associated with protein loss and loss of function. Class 2 mutations involve missense mutations, which are suggested to employ dominant-negative or gain-of-function effects. Some reports indicate a loss of function leading to reduced accessibility and diminished chromatin remodeling activity, mainly observed in lung cancer . In a comprehensive study of 4813 tumors from NSCLC patients, Schoenfeld et al. discovered that 212 patients (4% of the total population) exhibited class 1 SMARCA4 alterations (52% of the SMARCA4 variants) . In contrast, 195 patients (4% of the total population) had tumors with class 2 SMARCA4 alterations (48% of the SMARCA4 variants) . Of particular interest, SMARCA4 mutations are associated with altered MYC gene expression, which is essential in regulating cell growth and proliferation .
|
[
"Peter Manolakos",
"Luigi Boccuto",
"Diana S. Ivankovic"
] |
https://doi.org/10.3390/jpm14070684
|
N/A
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https://creativecommons.org/licenses/by/4.0/
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en
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1. Introduction
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Study
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SMARCA4 is a tumor suppressor gene located on chromosome 19p13.2 that encodes the Brahma-Related Gene 1 (BRG1) protein, which is one of two mutually exclusive critical DNA-dependent ATPases (Brahma is the other) that regulates gene expression by altering the chromatin structure . In addition, the BRG1 protein contains a bromodomain that plays a critical role in gene transcription and is essential in recognizing acetylated lysine residues on N-terminal tails of histones .
|
[
"Peter Manolakos",
"Luigi Boccuto",
"Diana S. Ivankovic"
] |
https://doi.org/10.3390/jpm14070684
|
N/A
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https://creativecommons.org/licenses/by/4.0/
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en
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1. Introduction
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biomedical
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Study
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BRG1 is part of the mammalian-type switch/sucrose non-fermenting (mSWI/SNF) chromatin-regulatory complex (CRC) . The mSWI/SNF remodeling complex is essential in regulating chromatin structures and contains approximately 10–12 subunits . Utilizing energy obtained through ATP hydrolysis, the catalytic subunits of human mSWI/SNF change nucleosome positioning. This alteration modulates the accessibility of transcriptional machinery to DNA, ultimately impacting the activation or repression of specific genes. The mSWI/SNF CRC protein subunits of interest are AT-Rich Interaction Domain 1A (ARID1A), SWI/SNF Related, Matrix-Associated, Actin-Dependent Regulator of Chromatin, Subfamily B, Member 1 (SMARCB1), and BRG1. They are among the most studied CRCs and have higher rates of mutations in human cancers than other CRC subunits .
|
[
"Peter Manolakos",
"Luigi Boccuto",
"Diana S. Ivankovic"
] |
https://doi.org/10.3390/jpm14070684
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
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1. Introduction
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Study
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The most frequent co-mutations found in the Massachusetts General Hospital analysis of 29 SMARCA4 patients that lacked BRG1 protein expression affected TP53 (N = 17, 59%), STK11 (N = 15, 52%), KEAP1 (N = 12, 41%), and KRAS (N = 10, 34%) . These co-mutation frequencies were validated in a more extensive Foundation Medicine data set with SMARCA4 co-mutations in TP53 (74%), CDKN2A (38%), STK11 (34%), KRAS (26%), and KEAP1 (15%) .
|
[
"Peter Manolakos",
"Luigi Boccuto",
"Diana S. Ivankovic"
] |
https://doi.org/10.3390/jpm14070684
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
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|
1. Introduction
| 4.109375 |
biomedical
|
Review
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Further research is needed to unravel the intricate interplay between SMARCA4 , chromatin remodeling, and tumorigenesis in non-small cell lung cancer. A comprehensive understanding of the nuanced interplay between SMARCA4 and KRAS co-occurring mutations in the context of NSCLC is paramount, as KRAS mutations commonly co-occur with various mutations and have been found to have a poor prognosis across several NSCLC studies . This review aims to summarize the clinical studies that have elucidated the potential implications of SMARCA4 mutations and SMARCA4 / KRAS co-mutations on survival outcomes when treating metastatic NSCLC patients across various treatments (i.e., chemotherapy and immune checkpoint inhibitors).
|
[
"Peter Manolakos",
"Luigi Boccuto",
"Diana S. Ivankovic"
] |
https://doi.org/10.3390/jpm14070684
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
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2. Materials and Methods
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PubMed and the Web of Science were searched using the following keywords: “SMARCA4” and “NSCLC”. Boolean operators were used to connect specific search keywords. Peer-reviewed articles published in English between 2018 and 2023 were included, and duplicate records were removed. Articles were included if they contained any of the following concerning NSCLC patients with SMARCA4 mutations vs. SMARCA4 WT: OS hazard ratio (HR), progression-free survival (PFS) HR, median OS, or median PFS. Articles were excluded if they were solely pre-clinical or diagnostic. Articles were also excluded if the majority of SMARCA4 lung cancer patients were diagnosed with non-NSCLC (i.e., small-cell), an undifferentiated tumor, or sarcomatoid SMARCA4 NSCLC. Articles were loaded into Raayan and reviewed by all authors. Discrepancies were discussed until a consensus was reached on included vs. excluded articles.
|
[
"Peter Manolakos",
"Luigi Boccuto",
"Diana S. Ivankovic"
] |
https://doi.org/10.3390/jpm14070684
|
N/A
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https://creativecommons.org/licenses/by/4.0/
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en
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2. Materials and Methods
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Study
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The search strategy was as follows: (smarca4 [Title/Abstract]) AND (nsclc [Title/Abstract]) Filters: Full text, Humans, from 2018–2023. The study selection process is outlined in the PRISMA flow diagram .
|
[
"Peter Manolakos",
"Luigi Boccuto",
"Diana S. Ivankovic"
] |
https://doi.org/10.3390/jpm14070684
|
N/A
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https://creativecommons.org/licenses/by/4.0/
|
en
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PMC11278206
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|
3.1. Results and Description of Studies
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|
Review
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In this critical review, 75 articles were identified by applying the search strategy. Twenty-eight articles were excluded and removed as duplicate records, and 47 articles were fully reviewed. Twenty-six articles were excluded due to the lack of SMARCA4 -mutation NSCLC survival outcomes, primary prognostic modeling, lack of incorrect patient population (i.e., sarcomatoid histology), review articles, and being written in non-English.
|
[
"Peter Manolakos",
"Luigi Boccuto",
"Diana S. Ivankovic"
] |
https://doi.org/10.3390/jpm14070684
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11278206_p10
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PMC11278206
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|
3.1. Results and Description of Studies
| 4.03125 |
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|
Review
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Twenty-one studies were included and reviewed in this critical review of SMARCA4 NSCLC. The included articles focus on survival outcomes across various patient categories, clinicopathologic characteristics, and immune checkpoint inhibitors (ICIs) cancer treatment. Moreover, a separate subheading focusing on SMARCA4 and KRAS co-mutation survival outcomes in patients with NSCLC is included, as this has recently become a medically relevant topic in the lung cancer community. Table 1 summarizes the NSCLC mutation analyzed, treatment, outcome, and relevance of each study in this review.
|
[
"Peter Manolakos",
"Luigi Boccuto",
"Diana S. Ivankovic"
] |
https://doi.org/10.3390/jpm14070684
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11278206_p11
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PMC11278206
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sec[2]/sec[1]/p[0]
|
3.2. SMARCA4 Mutations
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Schoenfeld et al. examined the clinicopathologic characteristics in a multivariate NSCLC analysis and determined that both SMARCA4 -mutated class 1 (N = 149) and class 2 (N = 143) had worse OS vs. WT ( p < 0.001) using Kaplan–Meir methods . In addition, class 1 SMARCA4 -mutated patients had the worst OS compared to class 2 mutated or WT patients (N = 996) via a log-rank test analysis . Furthermore, an ICI survival treatment analysis (N = 87) showed an OS improvement for SMARCA4 -mutated patients receiving ICI treatment vs. without ICI treatment regardless of class 1 or class 2 mutation status ( p = 0.01). However, there was no significant difference in PFS ( p = 0.74) or OS ( p = 0.35) for SMARCA4 -mutated patients receiving ICIs when comparing class 1 vs. class 2 alterations in an unadjusted analysis .
|
[
"Peter Manolakos",
"Luigi Boccuto",
"Diana S. Ivankovic"
] |
https://doi.org/10.3390/jpm14070684
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11278206_p12
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PMC11278206
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sec[2]/sec[1]/p[1]
|
3.2. SMARCA4 Mutations
| 4.121094 |
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Both studies from Alessi et al. further support SMARCA4 mutations as an independent factor that leads to worse outcomes for NSCLC patients . In one of the most extensive NSCLC studies of patients with SMARCA4 mutations who received chemo-immunotherapy (CIT), Alessi et al. reported that patients with non-squamous histology who had SMARCA4 mutations (N = 114) vs. WT (N = 593) had significantly worse survival: PFS (2.7 versus 6.1 months, HR: 1.62; p < 0.001), and OS (8.1 versus 15.0 months, HR: 1.70; p < 0.001) from the start of CIT . A multivariable analysis using inverse probability weighting was conducted to address potential selection bias due to the absence of Programmed Death Ligand-1 (PDL-1) reporting. The analysis revealed that confirmed SMARCA4 mutations independently correlated with reduced survival: PFS ( SMARCA4 -mutated HR: 1.61; p < 0.001), OS ( SMARCA4 -mutated HR: 1.66; p <0.001) to CIT .
|
[
"Peter Manolakos",
"Luigi Boccuto",
"Diana S. Ivankovic"
] |
https://doi.org/10.3390/jpm14070684
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11278206_p13
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PMC11278206
|
sec[2]/sec[1]/p[2]
|
3.2. SMARCA4 Mutations
| 4.109375 |
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A separate Alessi et al. study reported better OS in NSCLC patients with SMARCA4 WT vs. SMARCA4 -mutated patients (N = 163): SMARCA4 WT 25.0 months vs. SMARCA4 -mutated 15.6 months (HR: 0.064; p < 0.001) . However, in the immunotherapy-treated cohort of SMARCA4 -mutated (N = 57) and WT patients (N = 475), which included single-agent checkpoint therapy or ICI in combination with a Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4) inhibitor, there were no significant differences in SMARCA4 WT vs. SMARCA4 -mutated patients: PFS (3.1 vs. 2.1 months, HR: 0.93; p = 0.62) or OS (12.4 months vs. 11 months, HR: 0.83; p = 0.25) . When getting more granular and looking at different types of SMARCA4 mutations class 1 (N = 26) vs. class 2 (N = 31), there was no statistical OS difference in outcomes after receiving PDL-1 therapy when comparing SMARCA4 -mutated class 1 [nonsense, frameshift, and splice site] (6.7 months; p = 0.11) vs. WT patients (N = 275, 12.4 months) vs. SMARCA4 -mutated class 2 missense mutations (11.9 months, HR: 1.03; p = 0.87) .
|
[
"Peter Manolakos",
"Luigi Boccuto",
"Diana S. Ivankovic"
] |
https://doi.org/10.3390/jpm14070684
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11278206_p14
|
PMC11278206
|
sec[2]/sec[1]/p[3]
|
3.2. SMARCA4 Mutations
| 4.0625 |
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When examining class 1 or class 2 mutations regardless of the type of treatment, Fernando et al. compared patients with SMARCA4 WT vs. SMARCA4 NSCLC mutations in four categories: (a) homozygous truncated (N = 102), (b) homozygous nontruncated (N = 101), (c) heterozygous truncated (N = 16), and (d) heterozygous nontruncated (N = 49] . There was a significant OS difference when comparing SMARCA4 -mutated homozygous truncated vs. WT but no significant differences when comparing other SMARCA4 -mutated categories vs. SMARCA4 WT .
|
[
"Peter Manolakos",
"Luigi Boccuto",
"Diana S. Ivankovic"
] |
https://doi.org/10.3390/jpm14070684
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11278206_p15
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|
3.2. SMARCA4 Mutations
| 4.101563 |
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Fernando et al. conducted a separate analysis when looking at the same four SMARCA4 mutation categories but for patients who received immunotherapy (nivolumab, pembrolizumab, atezolizumab, or durvalumab) at any time during their cancer treatment . This ICI treatment analysis compared patients with SMARCA4 WT vs. SMARCA4 NSCLC mutations in four categories: (a) homozygous truncated (N = 38), (b) homozygous nontruncated (N = 41), (c) heterozygous truncated (N = 5), and (d) heterozygous nontruncated (N = 23). Similar to the non-treatment-specific OS analysis, there was a significant OS difference when comparing SMARCA4 -mutated homozygous truncated vs. SMARCA4 -WT (9.9 vs. 19.5 months, HR: 1.62; p = 0.01), but no significant differences when comparing WT with the other SMARCA4 -mutated categories in the ICI-treated patients .
|
[
"Peter Manolakos",
"Luigi Boccuto",
"Diana S. Ivankovic"
] |
https://doi.org/10.3390/jpm14070684
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11278206_p16
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PMC11278206
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sec[2]/sec[1]/p[5]
|
3.2. SMARCA4 Mutations
| 3.876953 |
biomedical
|
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|
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In a different study with the largest number of SMARCA4 mutations in this review , the authors focused on clinicopathologic characteristics of patients with SMARCA4 mutations and BRG1-deficient NSCLC . Even though this study had a large number of SMARCA4 patients, they only performed a SMARCA4 mutation PFS analysis (N = 16) with 11 patients on chemotherapy and five on CIT. These patients had extremely short PFS of only 38 and 35 days, respectively .
|
[
"Peter Manolakos",
"Luigi Boccuto",
"Diana S. Ivankovic"
] |
https://doi.org/10.3390/jpm14070684
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11278206_p17
|
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sec[2]/sec[1]/p[6]
|
3.2. SMARCA4 Mutations
| 4.121094 |
biomedical
|
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|
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Several studies included OS multivariate analysis across stages to address the outcomes of patients with SMARCA4 mutations in the context of Stage III vs. Stage IV disease. One study conducted by Liang et al. revealed that individuals with SMARCA4 mutations experienced significantly poorer survival in both locally advanced (Stage III) (N = 21) and metastatic (Stage IV) (N = 69) scenarios when compared to those with WT status . The median survival for SMARCA4 -mutated vs. WT patients was notably lower in Stage III (23.73 vs. 29.43 months, p < 0.01) and Stage IV (11.93 vs. 28.23 months, p < 0.01) . To support this finding in Stage III patients, Talvitie et al.’s multivariate analysis on SMARCA4 -mutated patients (N = 31) also revealed worse OS vs. WT patients (HR:1.93; p = 0.04) . Regardless of stage, both authors conducted a multivariate analysis showing that SMARCA4 WT (N = 221) patients had a better OS than mutated patients [(N = 105), 28.23 months vs. 12.17 months; p < 0.001] and SMARCA4 -mutated patients had a worse OS than WT (HR: 3.522; p < 0.002) .
|
[
"Peter Manolakos",
"Luigi Boccuto",
"Diana S. Ivankovic"
] |
https://doi.org/10.3390/jpm14070684
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11278206_p18
|
PMC11278206
|
sec[2]/sec[1]/p[7]
|
3.2. SMARCA4 Mutations
| 4.097656 |
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In association with SMARCA4 mutations and clinico-genomic biomarkers across two different studies, tumor mutational burden (TMB) and brain metastasis in Anaplastic Lymphoma Kinase (ALK)-positive NSCLC were evaluated . In exploring the relevance of TMB, Xu et al. conducted an NSCLC adenocarcinoma multivariate analysis . The four arms were as follows: (a) SMARCA4 WT, TMB Low (N = 761), (b) SMARCA4 WT, TMB High (N = 722), (c) SMARCA4 -mutated, TMB Low (N = 26), and (d) SMARCA4 -mutated, TMB High (N = 69) . The results showed a statistically better overall survival for SMARCA4 WT, TMB High . In the context of brain metastasis, one study examined clinico-genomic outcomes in patients with (ALK)-positive NSCLC treated with alectinib . They determined that SMARCA4 -mutated patients (N = 3) with brain metastasis were the only group with co-mutations ( SMARCA4 / ALK ) to do statistically worse across a multivariate analysis (HR: 8.76; p = 0.009).
|
[
"Peter Manolakos",
"Luigi Boccuto",
"Diana S. Ivankovic"
] |
https://doi.org/10.3390/jpm14070684
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11278206_p19
|
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|
3.2. SMARCA4 Mutations
| 4.066406 |
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When addressing SMARCA4 mutation OS differences in a multivariate analysis of biological sex, two OS results were mixed between the sexes . Pan et al. conducted a retrospective multivariate analysis, which included a cohort across 21 medical centers. There were 44 NSCLC patients with SMARCA4 mutations, and men (N = 25) had a significantly worse OS than women (N = 19) (2.75 months vs. inestimable, HR:14.2; p = 0.02) . The authors shared that one reason for the inestimable survival may be the low sample size of SMARCA4 NSCLC patients. In the second study, the authors conducted a multivariate analysis, which resulted in statistically worse OS for women (N = 88) vs. men (N = 25) (HR: 4.1; p = 0.04) .
|
[
"Peter Manolakos",
"Luigi Boccuto",
"Diana S. Ivankovic"
] |
https://doi.org/10.3390/jpm14070684
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11278206_p20
|
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|
sec[2]/sec[1]/p[9]
|
3.2. SMARCA4 Mutations
| 4.089844 |
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0.00005078315734863281
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There were two NSCLC analyses of the OAK study involving atezolizumab. In the first OAK study analysis, Wang et al. discovered that SMARCA4 was more likely to be seen in the negative PDL-1 expression group, but there was no statistical difference in OS when comparing atezolizumab vs. docetaxel in SMARCA4 -mutated (N = 100) whether the patients were PDL-1 high or negative (HR = 0.67; p = 0.256) . In addition, there was no difference in OS in SMARCA4 -mutated NSCLC patients (N = 39) vs. SMARCA4 WT (N = 491) whether the patients were PDL-1 high or negative when treated with atezolizumab (HR = 1.185, p = 0.513) . In a second OAK uni-variate analysis, SMARCA4 -mutated patients (N = 18) receiving atezolizumab did not fare worse than SMARCA4 WT patients (N = 181) (HR: 1.70; p = 0.064) .
|
[
"Peter Manolakos",
"Luigi Boccuto",
"Diana S. Ivankovic"
] |
https://doi.org/10.3390/jpm14070684
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11278206_p21
|
PMC11278206
|
sec[2]/sec[1]/p[10]
|
3.2. SMARCA4 Mutations
| 4.121094 |
biomedical
|
Study
|
[
0.99951171875,
0.0004012584686279297,
0.00020372867584228516
] |
[
0.9990234375,
0.0002560615539550781,
0.0005893707275390625,
0.00007480382919311523
] |
In the analysis by Velut et al., NSCLC patients with SMARCA4 mutations (N = 7) did worse than WT (N = 70), independent of whether they received ICI therapy or not (HR: 3.2; p = 0.006) . Interestingly, OS rates at 1 year were not significantly different between SMARCA4 -mutated and WT patients but dropped significantly at 2 (58% vs. 74%) and 5 years (37% vs. 53%). In addition, patients were significantly younger upon diagnosis with SMARCA4 mutation vs. without (61.9 years vs. 66.6 years; p = 0.01) . A second single-institution analysis demonstrated a numerical, but not statistical, PFS benefit (6.3 vs. 3.9 months, HR: 0.64; p = 0.15) in SMARCA4 WT (N = 130) vs. SMARCA4 -mutated (N = 16) patients receiving ICIs (87% received combination ICI-chemotherapy) .
|
[
"Peter Manolakos",
"Luigi Boccuto",
"Diana S. Ivankovic"
] |
https://doi.org/10.3390/jpm14070684
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11278206_p22
|
PMC11278206
|
sec[2]/sec[1]/p[11]
|
3.2. SMARCA4 Mutations
| 4.117188 |
biomedical
|
Study
|
[
0.99951171875,
0.0002834796905517578,
0.00021564960479736328
] |
[
0.99853515625,
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0.0010900497436523438,
0.00007009506225585938
] |
Three additional studies demonstrated significantly worse OS outcomes for NSCLC patients with SMARCA4 mutations than wild-type patients across a multivariate analysis. In the first study, Yang et al.’s analysis resulted in worse OS for mutated (N = 5) vs. WT (N = 32) patients (4.5 months vs. 13.3 months, HR: 2.86; p = 0.031) . The second multivariate analysis obtained a worse PFS (3 vs. 8 months; p = 0.007) for SMARCA4 -mutated (N = 4) vs. WT patients (N = 99), and the results concluded that SMARCA4 mutations were independently associated with a worse OS (HR: 3.098; p = 0.038) . The last SMARCA4 mutation analysis highlighted that the differences in all-cause mortality remained significant between the adenocarcinoma NSCLC patients that were mutated (N = 21) vs. wild-type (N = 204) (HR: 2.06; p = 0.003) .
|
[
"Peter Manolakos",
"Luigi Boccuto",
"Diana S. Ivankovic"
] |
https://doi.org/10.3390/jpm14070684
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11278206_p23
|
PMC11278206
|
sec[2]/sec[2]/p[0]
|
3.3. SMARCA4/KRAS Co-Mutations
| 4.101563 |
biomedical
|
Study
|
[
0.99951171875,
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] |
[
0.9951171875,
0.00026154518127441406,
0.0045013427734375,
0.00009715557098388672
] |
Seven NSCLC publications contained SMARCA4 / KRAS co-mutation survival outcomes . Two of these studies had specific SMARCA4 / KRAS point mutation outcomes (i.e., KRAS G12C and G12D), and one analyzed survival with co-mutations in patients across clinical characteristics (i.e., brain and liver mets) . Moreover, two different co-mutated analyses were performed by Alessi et al., highlighting robust results across many types and combinations of ICIs and chemotherapy . Across various treatments, Schoenfeld et al.’s multivariate SMARCA4 / KRAS co-mutation analysis resulted in worse statistical OS regardless of class 1 (N = 58) or 2 alterations (N = 52) (class 1: HR: 1.59 and class 2: HR: 2.75 vs. WT; p < 0.001) .
|
[
"Peter Manolakos",
"Luigi Boccuto",
"Diana S. Ivankovic"
] |
https://doi.org/10.3390/jpm14070684
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999995 |
PMC11278206_p24
|
PMC11278206
|
sec[2]/sec[2]/p[1]
|
3.3. SMARCA4/KRAS Co-Mutations
| 4.09375 |
biomedical
|
Study
|
[
0.99951171875,
0.00022470951080322266,
0.00017881393432617188
] |
[
0.9990234375,
0.0002321004867553711,
0.0006890296936035156,
0.0000699758529663086
] |
Negrao et al. produced the only publication focusing on NSCLC patients with co-mutations and KRAS G12C inhibitors (sotorasib or adagrasib). All NSCLC patients in their study had KRAS G12C mutations . SMARCA4 / KRAS G12C co-mutated patients (N = 18) had significantly worse PFS than SMARCA4 WT/ KRAS G12C-mutated patients (N = 213) (1.6 vs. 5.4 months, HR: 3.04; p < 0.001) and had a significantly worse OS (4.9 months vs. 11.8 months, HR: 3.07; p < 0.001) . In relation to these survival outcomes, SMARCA4 was one of the three tumor suppressor genes significantly enriched in the early progressing subgroup ( p = 0.001) .
|
[
"Peter Manolakos",
"Luigi Boccuto",
"Diana S. Ivankovic"
] |
https://doi.org/10.3390/jpm14070684
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11278206_p25
|
PMC11278206
|
sec[2]/sec[2]/p[2]
|
3.3. SMARCA4/KRAS Co-Mutations
| 4.042969 |
biomedical
|
Study
|
[
0.99951171875,
0.0002472400665283203,
0.00024819374084472656
] |
[
0.99951171875,
0.00031185150146484375,
0.00035071372985839844,
0.000055670738220214844
] |
The second study that contained granular co-mutation outcomes ( KRAS G12D) demonstrated statistically worse PFS for NSCLC patients; PFS: SMARCA4 / KRAS G12D-co-mutated (N = 8) vs. SMARCA4 WT/ KRAS G12D-mutated (N = 49) . However, OS was only numerically worse but not statistically significant: SMARCA4 / KRAS G12D-co-mutated vs. SMARCA4 WT/ KRAS G12D-mutated .
|
[
"Peter Manolakos",
"Luigi Boccuto",
"Diana S. Ivankovic"
] |
https://doi.org/10.3390/jpm14070684
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11278206_p26
|
PMC11278206
|
sec[2]/sec[2]/p[3]
|
3.3. SMARCA4/KRAS Co-Mutations
| 4.101563 |
biomedical
|
Study
|
[
0.99951171875,
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] |
[
0.99951171875,
0.00023353099822998047,
0.000377655029296875,
0.00006836652755737305
] |
Boiarsky et al. demonstrated that more than two times the number of patients had co-mutated SMARCA4 / KRAS NSCLC Stage IV disease upon diagnosis (14%, N = 214) vs. Stage I (5%, N = 83) ( p = 0.038), and these co-mutated patients had worse outcomes across patterns of metastatic spread (i.e., the brain) . For example, OS was significantly worse for SMARCA4 / KRAS -co-mutated (N = 33) patients with brain metastasis vs. SMARCA4 WT/ KRAS -mutated (N = 231) patients . This HR was similar to SMARCA4 / KRAS -co-mutated (N = 25) patients with liver metastasis vs. SMARCA4 WT/ KRAS -mutated (N = 155) patients .
|
[
"Peter Manolakos",
"Luigi Boccuto",
"Diana S. Ivankovic"
] |
https://doi.org/10.3390/jpm14070684
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11278206_p27
|
PMC11278206
|
sec[2]/sec[2]/p[4]
|
3.3. SMARCA4/KRAS Co-Mutations
| 4.164063 |
biomedical
|
Study
|
[
0.99951171875,
0.0003681182861328125,
0.0002168416976928711
] |
[
0.9990234375,
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] |
SMARCA4 -mutated patients had worse CIT treatment outcomes than SMARCA4 WT patients in both KRAS WT and KRAS -mutated non-squamous NSCLC . In reference to how co-mutated SMARCA4 / KRAS non-squamous patients (N = 44) fared vs. SMARCA4 WT/ KRAS -mutated patients (N = 232), they fared even worse: PFS: SMARCA4 / KRAS -mutated vs. SMARCA4 WT/ KRAS -mutated (2.2 vs. 6.2 months, HR: 2.39; p < 0.001), OS: SMARCA4 / KRAS -mutated vs. SMARCA4 WT/ KRAS -mutated (6.6 vs. 14.6 months, HR: 2.52; p < 0.001) . In the second Alessi et al. analysis with single-agent ICI or ICI-combination with CTLA-4, KRAS -mutant NSCLC was the most common co-mutation in the SMARCA4 mutant subset (N = 17) . The SMARCA4 / KRAS -co-mutated patients had significantly shorter PFS (1.4 versus 4.1 months, HR: 0.25; p < 0.001) and OS (3 versus 15.1 months, HR: 0.29; p < 0.001) compared with NSCLC patients with SMARCA4 WT/ KRAS mutations (N = 159). Thus, the presence of a SMARCA4 / KRAS co-mutation may confer a worse outcome to ICIs .
|
[
"Peter Manolakos",
"Luigi Boccuto",
"Diana S. Ivankovic"
] |
https://doi.org/10.3390/jpm14070684
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999995 |
PMC11278206_p28
|
PMC11278206
|
sec[2]/sec[2]/p[5]
|
3.3. SMARCA4/KRAS Co-Mutations
| 4.136719 |
biomedical
|
Study
|
[
0.99951171875,
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] |
[
0.99951171875,
0.00027251243591308594,
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0.0000540614128112793
] |
The last analysis from Liu et al. demonstrated significantly worse OS for all four SMARCA4 / KRAS -mutated adenocarcinoma NSCLC cohorts across ICI-treated and non-ICI-treated NSCLC patients . In Cohort A, SMARCA4 / KRAS -co-mutated vs. SMARCA4 WT/ KRAS -mutated patients had worse OS (15.73 vs. 19.73 months) in a non-immunotherapy cohort in The Cancer Genome Atlas (TCGA) (HR: 2.32, p = 0.047). In Cohort B, SMARCA4 / KRAS -co-mutated vs. SMARCA4 WT/ KRAS -mutated patients had worse OS (5.2 vs. 6.5 months) in a non-immunotherapy MSK-CT cohort (HR: 1.95, p = 0.015). In Cohort C, SMARCA4 / KRAS co-mutated vs. SMARCA4 WT/ KRAS -mutated patients (1.73 vs. 4.22 months) had worse PFS in an immunotherapy MSK-IO cohort (HR: 2.15; p = 0.048). In Cohort D, SMARCA4 / KRAS -co-mutated vs. SMARCA4 WT/ KRAS -mutated patients had worse OS in the immunotherapy Wake Forest cohort .
|
[
"Peter Manolakos",
"Luigi Boccuto",
"Diana S. Ivankovic"
] |
https://doi.org/10.3390/jpm14070684
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11278206_p29
|
PMC11278206
|
sec[3]/p[0]
|
4. Discussion
| 4.144531 |
biomedical
|
Review
|
[
0.99267578125,
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] |
[
0.01497650146484375,
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This SMARCA4 NSCLC critical review focuses on survival outcomes across clinicopathological characteristics, KRAS co-mutations, and treatment with ICIs within twenty-one peer-reviewed articles. Eleven of thirteen (85%) SMARCA4 mutation survival analyses in this review demonstrated significantly worse overall survival for SMARCA4 -mutated NSCLC patients regardless of cancer treatment type. There were somewhat mixed results across SMARCA4 -mutated treatment analysis for patients receiving ICIs and ICIs in combination with chemotherapy or CTLA-4 treatment. Three of the seven ICI analyses had worse OS for SMARCA4 -mutated patients, three had no OS differences, and one outlier study highlighted that the patients with SMARCA4 mutations did better on ICIs regardless of the class of SMARCA4 mutation. Regarding SMARCA4 / KRAS co-mutations, all seven treatment analyses (four with ICIs, two with non-ICIs, and one with KRAS G12C inhibitors) indicated that co-mutated SMARCA4 / KRAS NSCLC patients consistently had significantly worse OS than SMARCA4 WT/ KRAS -mutated cohorts .
|
[
"Peter Manolakos",
"Luigi Boccuto",
"Diana S. Ivankovic"
] |
https://doi.org/10.3390/jpm14070684
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999999 |
PMC11278206_p30
|
PMC11278206
|
sec[3]/sec[0]/p[0]
|
4.1. SMARCA4 Molecular Sub-Types and Genomic Features
| 4.074219 |
biomedical
|
Review
|
[
0.998046875,
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] |
[
0.165771484375,
0.0014743804931640625,
0.83203125,
0.0006341934204101562
] |
In the largest SMARCA4 -mutated survival analysis in this review (N = 407), the authors determined that class 1 truncating mutations were the strongest independent factor for significantly worse OS for NSCLC patients . Class 1 mutations are typically associated with BRG1 protein loss compared to class 2 mutations, not losing any BRG1 protein expression (81% vs. 0%, p < 0.001) . This lack of protein expression was also seen in an analysis completed at Massachusetts General Hospital (MGH), where 84% of patients with class 1 truncating mutations lacked BRG1 protein expression . However, class 2 mutations (missense, nontruncating) also had worse OS, indicating that protein function could be impacted even though protein expression was evident .
|
[
"Peter Manolakos",
"Luigi Boccuto",
"Diana S. Ivankovic"
] |
https://doi.org/10.3390/jpm14070684
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11278206_p31
|
PMC11278206
|
sec[3]/sec[0]/p[1]
|
4.1. SMARCA4 Molecular Sub-Types and Genomic Features
| 3.988281 |
biomedical
|
Review
|
[
0.99560546875,
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0.002471923828125
] |
[
0.03619384765625,
0.0013170242309570312,
0.9619140625,
0.0003750324249267578
] |
As the only outlier in this review, SMARCA4 -mutated NSCLC patients treated with ICI therapy had a longer OS ( p = 0.01) . In contrast, this ICI treatment OS benefit is not seen as appreciable when looking at SMARCA4 WT vs. class 1 or 2 SMARCA4 mutations. Alessi et al. point out that Schoenfeld’s results may differ from their extensive SMARCA4 ICI therapy analysis due to imbalances in unreported baseline clinicopathological characteristics in the Schoenfeld publication, which could have altered the OS .
|
[
"Peter Manolakos",
"Luigi Boccuto",
"Diana S. Ivankovic"
] |
https://doi.org/10.3390/jpm14070684
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999995 |
PMC11278206_p32
|
PMC11278206
|
sec[3]/sec[0]/p[2]
|
4.1. SMARCA4 Molecular Sub-Types and Genomic Features
| 4.089844 |
biomedical
|
Study
|
[
0.99951171875,
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[
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As further support, both Alessi et al. studies highlight SMARCA4 mutations as an independent factor in a significantly worse outcome for NSCLC patients . However, different conclusions arose in their two separate publication analyses of ICI treatment: (1) based on whether it was used in the first line with chemotherapy (CIT), or (2) in pre-treated patients as a single agent (ICI) or ICI/CTLA4 combination therapy. In the first-line setting, SMARCA4 mutations were associated with significantly worse OS to first-line CIT treatment in non-squamous NSCLC ( SMARCA4 -mutated 8.1 months vs. SMARCA4 WT 15.0 months ( p < 0.001) . In the pre-treatment setting, the authors did not find an association between SMARCA4 mutational status and ICI treatment on PFS or OS, or whether the patient had a class 1 or 2 SMARCA4 mutation .
|
[
"Peter Manolakos",
"Luigi Boccuto",
"Diana S. Ivankovic"
] |
https://doi.org/10.3390/jpm14070684
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11278206_p33
|
PMC11278206
|
sec[3]/sec[0]/p[3]
|
4.1. SMARCA4 Molecular Sub-Types and Genomic Features
| 4.085938 |
biomedical
|
Study
|
[
0.99951171875,
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[
0.99951171875,
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] |
When looking more granularly at truncated vs. nontruncated SMARCA4 mutations or homozygous vs. heterozygous, there was a significantly worse OS when comparing SMARCA4 homozygous truncated vs. WT but no significant differences when comparing other SMARCA4 -mutated categories vs. WT . This significant OS difference was also demonstrated when looking specifically at ICI treatment when comparing homozygous truncated vs. WT (9.9 vs. 19.5 months, HR: 1.62; p = 0.01), but no significant differences were obtained when comparing WT with the other SMARCA4 -mutated categories in the ICI-treated patients .
|
[
"Peter Manolakos",
"Luigi Boccuto",
"Diana S. Ivankovic"
] |
https://doi.org/10.3390/jpm14070684
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11278206_p34
|
PMC11278206
|
sec[3]/sec[0]/p[4]
|
4.1. SMARCA4 Molecular Sub-Types and Genomic Features
| 3.769531 |
biomedical
|
Study
|
[
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[
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] |
TMB is a genomic feature being analyzed in NSCLC across various ICI studies . It is being reviewed as a possible biomarker for the use of ICIs in SMARCA4 -mutated NSCLC . Xu et al. showed a worse OS for NSCLC patients that are SMARCA4 -mutated (TMB Low or TMB High) as compared to SMARCA4 WT/TMB High .
|
[
"Peter Manolakos",
"Luigi Boccuto",
"Diana S. Ivankovic"
] |
https://doi.org/10.3390/jpm14070684
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11278206_p35
|
PMC11278206
|
sec[3]/sec[1]/p[0]
|
4.2. Clinicopathological Features
| 4.050781 |
biomedical
|
Study
|
[
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[
0.99462890625,
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Multiple studies, including Liang et al. and Talvitie et al., conducted OS multivariate analyses across different stages, revealing consistently poorer survival for patients with SMARCA4 mutations . Liang et al.’s study demonstrated significantly worse OS in both locally advanced (Stage III) and metastatic (Stage IV) SMARCA4 -mutated scenarios compared to WT status (Stage III (23.73 vs. 29.43 months, p < 0.01) and Stage IV (12.17 vs. 28.23 months, p < 0.01) . Talvitie et al.’s analysis in Stage III patients further supported worse OS for SMARCA4 -mutated patients . Regardless of which stage, multivariate analyses consistently showed worse OS for SMARCA4 -mutated patients, highlighting the impact of these mutations on survival outcomes.
|
[
"Peter Manolakos",
"Luigi Boccuto",
"Diana S. Ivankovic"
] |
https://doi.org/10.3390/jpm14070684
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11278206_p36
|
PMC11278206
|
sec[3]/sec[1]/p[1]
|
4.2. Clinicopathological Features
| 4.128906 |
biomedical
|
Review
|
[
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[
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This SMARCA4 review illustrated statistically significant OS differences based on brain metastasis and mixed results based on biological sex . In the context of brain metastases, Miao et al. investigated clinicogenomic outcomes in ALK -positive NSCLC patients treated with alectinib, finding that SMARCA4 -mutated patients with brain metastases were the only group with co-mutations to exhibit statistically worse outcomes in a multivariate analysis (HR: 8.76; p = 0.009) . In two multivariate analyses of the impact of biological sex on SMARCA4 mutation OS differences, one analysis demonstrated significantly worse survival for men, and the other demonstrated worse survival for women . Pan et al. reported that male NSCLC patients with SMARCA4 mutations had a markedly worse OS than females (HR: 12.64; p = 0.002), while Liang et al.’s study highlighted a worse OS for women across a cohort of Stage IV SMARCA4 -mutated patients (HR:14.2; p = 0.02) . Although women had a statistically significant worse OS in the multivariate analysis, the authors share that one of the reasons for the possible large female survival discrepancy was due to lower numbers of females than males in the study (88 vs. 133) .
|
[
"Peter Manolakos",
"Luigi Boccuto",
"Diana S. Ivankovic"
] |
https://doi.org/10.3390/jpm14070684
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11278206_p37
|
PMC11278206
|
sec[3]/sec[1]/p[2]
|
4.2. Clinicopathological Features
| 4.066406 |
biomedical
|
Study
|
[
0.99951171875,
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] |
[
0.99560546875,
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] |
In the context of SMARCA4 NSCLC patients treated with immune checkpoint inhibitors (ICIs), one study found that those with SMARCA4 mutations had worse outcomes than WT patients regardless of ICI treatment or not (HR = 3.2; p = 0.006), and two separate OAK trial NSCLC analyses showed no OS differences with atezolizumab (ICI) vs. docetaxel in pre-treated NSCLC SMARCA4 -mutated patients . Three additional studies demonstrated significantly worse OS outcomes for NSCLC patients with SMARCA4 mutations vs. WT patients across a multivariate analysis and various standards of care treatments .
|
[
"Peter Manolakos",
"Luigi Boccuto",
"Diana S. Ivankovic"
] |
https://doi.org/10.3390/jpm14070684
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999999 |
PMC11278206_p38
|
PMC11278206
|
sec[3]/sec[2]/p[0]
|
4.3. SMARCA4/KRAS Co-Mutations
| 4.097656 |
biomedical
|
Review
|
[
0.9951171875,
0.002719879150390625,
0.0023860931396484375
] |
[
0.024871826171875,
0.0010404586791992188,
0.9736328125,
0.0004284381866455078
] |
All seven SMARCA4 / KRAS co-mutation NSCLC publications in this review showed either a significantly worse PFS or OS as compared to SMARCA4 WT/ KRAS mutation analyses across standard-of-care cancer treatments or within a specific treatment analysis (i.e., KRAS G12C inhibitor, ICIs, or non-ICIs) . Two of these studies presented granular survival outcomes specific to two KRAS isoforms (G12C and G12D) . Finally, one analysis demonstrated significantly worse survival for SMARCA4 / KRAS -co-mutated patients as they presented at a higher rate of Stage IV NSCLC with a significantly higher propensity of brain or liver metastasis . These higher rates of metastatic spread led to significantly worse survival for co-mutated SMARCA4 / KRAS vs. SMARCA4 WT/ KRAS -mutated patients who either had brain or liver metastasis .
|
[
"Peter Manolakos",
"Luigi Boccuto",
"Diana S. Ivankovic"
] |
https://doi.org/10.3390/jpm14070684
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11278206_p39
|
PMC11278206
|
sec[3]/sec[2]/p[1]
|
4.3. SMARCA4/KRAS Co-Mutations
| 4.144531 |
biomedical
|
Review
|
[
0.99609375,
0.001834869384765625,
0.0020236968994140625
] |
[
0.047149658203125,
0.0014352798461914062,
0.951171875,
0.0004277229309082031
] |
SMARCA4 / KRAS co-mutations are among the most common co-mutations within this review. Among the largest co-mutation analyses within the review, SMARCA4 / KRAS was co-mutated at a rate of 36% in NSCLC . Within this multi-variate analysis and across various treatments, the SMARCA4 / KRAS co-mutation analysis by Schoenfeld et al. resulted in worse OS regardless of class 1 or 2 alteration [class 1: HR: 1.59, and class 2: HR: 2.75] vs. WT ( p < 0.001) . Cooper et al.’s PFS co-mutation SMARCA4 / KRAS G12D analysis demonstrated significantly worse outcomes for co-mutated patients vs. SMARCA4 WT/ KRAS G12D-mutated patients . However, as the outlier in this critical review focusing on KRAS G12D, the SMARCA4 / KRAS G12C co-mutation OS analysis did not result in a significant difference as compared to SMARCA4 WT/ KRAS -mutated NSCLC patients (6.1 vs. 17.3 months; p = 0.42) .
|
[
"Peter Manolakos",
"Luigi Boccuto",
"Diana S. Ivankovic"
] |
https://doi.org/10.3390/jpm14070684
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11278206_p40
|
PMC11278206
|
sec[3]/sec[3]/p[0]
|
4.4. SMARCA4/KRAS Co-Mutation Treatment Analysis
| 4.117188 |
biomedical
|
Study
|
[
0.99951171875,
0.00026679039001464844,
0.0002199411392211914
] |
[
0.99853515625,
0.00022304058074951172,
0.0013837814331054688,
0.00006967782974243164
] |
Four studies reported six SMARCA4 / KRAS co-mutation OS survival treatment analyses . All six treatment analyses across various treatment types (i.e., ICI, non-ICI, or KRAS G12C inhibitor) resulted in a significantly worse OS ( p < 0.05) for SMARCA4 / KRAS -co-mutated NSCLC patients. Negrao et al. had the only publication focusing on KRAS G12C NSCLC patients with co-mutations and KRAS G12C inhibitors (sotorasib or adagrasib) . NSCLC patients with SMARCA4 / KRAS G12C co-mutations vs. SMARCA4 WT/ KRAS G12C mutations had significantly worse OS (4.9 months vs. 11.8 months, HR: 3.07; p < 0.001). In relation to these survival outcomes, SMARCA4 was one of the three tumor suppressor genes significantly enriched in the early progressing subgroup ( p = 0.001) .
|
[
"Peter Manolakos",
"Luigi Boccuto",
"Diana S. Ivankovic"
] |
https://doi.org/10.3390/jpm14070684
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
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