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|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
39057315_p49
|
39057315
|
sec[4]/sec[2]/p[2]
|
5.3. Liposomes
| 4.105469 |
biomedical
|
Study
|
[
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[
0.99853515625,
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Atashbeyk, D.G. and colleagues carried out a study on the antibacterial activity of oleic acid and GS against methicillin-resistant S. aureus (MRSA). The researchers discovered that the combination of GS and oleic acid had synergistic effects against MRSA. When GS was combined into liposomal forms, its minimum inhibitory concentration (MIC) values were reduced 15-fold, whereas gentamicin and oleic acid reduced the MIC values 27-fold. The liposomal combination inhibited and killed bacteria more effectively than VM (commonly used to treat MRSA), making it the most efficient compound in the time–kill testing. The liposomal formulations can improve antibacterial action, lower the effective concentration required, and cause rapid bacterial inhibition.
|
[
"Silvia Pisani",
"Shafia Tufail",
"Mariella Rosalia",
"Rossella Dorati",
"Ida Genta",
"Enrica Chiesa",
"Bice Conti"
] |
https://doi.org/10.3390/jfb15070194
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
39057315_p50
|
39057315
|
sec[4]/sec[2]/p[3]
|
5.3. Liposomes
| 4.09375 |
biomedical
|
Study
|
[
0.99951171875,
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[
0.99853515625,
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Nicolosi, D. and colleagues carried a study on the antibacterial properties of VM encapsulated in fusogenic liposomes, commonly known as SUVETs. The method of preparation includes encapsulating VM in these liposomes. Fusogenic liposomes have a positive charge, which improves Gram-negative bacterial targeting and allows for close membrane interactions via charge attraction. This encapsulation procedure improved vancomycin’s capacity to enter Gram-negative bacteria, which was previously ineffective due to its inability to pass the bacterial cell membrane. As a result, VM’s antibacterial activity was increased by including Gram-negative bacteria. This novel strategy may lead to more effective therapies for infections caused by Gram-negative bacteria that were ineffective previously.
|
[
"Silvia Pisani",
"Shafia Tufail",
"Mariella Rosalia",
"Rossella Dorati",
"Ida Genta",
"Enrica Chiesa",
"Bice Conti"
] |
https://doi.org/10.3390/jfb15070194
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
39057315_p51
|
39057315
|
sec[4]/sec[2]/p[4]
|
5.3. Liposomes
| 4.113281 |
biomedical
|
Study
|
[
0.99951171875,
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[
0.9990234375,
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Abrishami, M. and colleagues carried out a study to assess the in vivo efficacy of a liposomal formulation of VM against methicillin-resistant S. aureus (MRSA) in rabbits. The rabbits received a liquid culture medium containing MRSA, and after 48 h, the eyes were treated with a nano-liposomal formulation and free VM. The rabbits were euthanized at predetermined intervals of 12, 24, 48, 96, and 144 h following injection. The antibacterial activity for different VM formulations was assessed using the time-killing method. The liposomal VM had a zeta potential of 29.7 mV, mean liposome size of 381.93 ± 30.13 nm, and 47% encapsulation efficiency. The results of time-killing studies indicated that the liposomal formula was more effective than VM in a free form. Thus, it was concluded that the nanoliposomal formulation is a significant antibacterial agent to combat infectious endophthalmitis.
|
[
"Silvia Pisani",
"Shafia Tufail",
"Mariella Rosalia",
"Rossella Dorati",
"Ida Genta",
"Enrica Chiesa",
"Bice Conti"
] |
https://doi.org/10.3390/jfb15070194
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
39057315_p52
|
39057315
|
sec[4]/sec[2]/p[5]
|
5.3. Liposomes
| 4.089844 |
biomedical
|
Study
|
[
0.99951171875,
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[
0.99951171875,
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Vancomycin-loaded PEGylated liposomes (PEG-VM-lipos) were effective in reducing vancomycin-induced kidney damage. The study performed by Joshi and colleagues tested, at first, PEG-VM-lipo in vitro cytotoxicity on kidney cells with PEG-VM-lipo and discovered that it was less toxic than conventional VM. Secondly, male adult rats were given either PEG-VANCO-lipo or VM HCl. Plasma VM concentrations and KIM-1, an injury biomarker in urine, were compared. On day three, the PEG-Vanco-lipo group had less VM in their urine and kidneys, as well as KIM-1, than the VM group. On the first and third days, the VM group had significantly lower plasma VM concentrations than the PEG-VM-lipo group .
|
[
"Silvia Pisani",
"Shafia Tufail",
"Mariella Rosalia",
"Rossella Dorati",
"Ida Genta",
"Enrica Chiesa",
"Bice Conti"
] |
https://doi.org/10.3390/jfb15070194
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
39057315_p53
|
39057315
|
sec[4]/sec[2]/p[6]
|
5.3. Liposomes
| 4.101563 |
biomedical
|
Study
|
[
0.99951171875,
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[
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Strategies to improve VM loading into liposomes have been used. In example Sybil Obuobi and colleagues designed and developed a nanostructured hybrid system wherein nucleic acid nanogels are caged within a liposomal vesicle for VM intracellular delivery. The authors exploited the different charges of DNA nanogels and VM to improve VM loading into liposomes made from pure soy phosphatidylcholine. The binding affinity between the DNA nanostructures and VM significantly increased the antibiotic loading and resulted in a relatively slower release profile than the liposomal or nanogel formulations alone. DNA nanogels encapsulated in liposomal vesicles were proposed as a universal loading platform for the intracellular delivery of antibiotics .
|
[
"Silvia Pisani",
"Shafia Tufail",
"Mariella Rosalia",
"Rossella Dorati",
"Ida Genta",
"Enrica Chiesa",
"Bice Conti"
] |
https://doi.org/10.3390/jfb15070194
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
39057315_p54
|
39057315
|
sec[4]/sec[3]/p[0]
|
5.4. Dendrimers
| 4.109375 |
biomedical
|
Study
|
[
0.99951171875,
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0.00018227100372314453
] |
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0.99853515625,
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Among the promising nanocarriers, dendrimers have emerged as a class of versatile and tunable materials with unique properties that make them well-suited for delivering GS and VM . Dendrimers are well-defined, highly branched, and monodisperse synthetic macromolecules with a core, branching units, and peripheral functional groups . A recent study was conducted by Sheykhloo, H. and colleagues to develop GS-conjugated poly(amidoamine) (PAMAM) dendrimers to improve the therapeutic efficacy of GS against P. aeruginosa . Gentamicin-presenting dendrimers were created by utilizing MAL-PEG3400-NHS as a redox-sensitive linker to attach GS to the surface of G4 PAMAM dendrimers. Gentamicin linked to the surface of PAMAM dendrimers exhibited three times the antibacterial activity of non-conjugated GS. The PAMAM-GS dendrimers were found to be at least 13 times more effective against biofilms than GS under normal conditions.
|
[
"Silvia Pisani",
"Shafia Tufail",
"Mariella Rosalia",
"Rossella Dorati",
"Ida Genta",
"Enrica Chiesa",
"Bice Conti"
] |
https://doi.org/10.3390/jfb15070194
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999999 |
39057315_p55
|
39057315
|
sec[4]/sec[3]/p[1]
|
5.4. Dendrimers
| 4.105469 |
biomedical
|
Study
|
[
0.99951171875,
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] |
[
0.99658203125,
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] |
Chosy, M.B. and colleagues carried out a study to expand the antibiotic potential of VM. The authors were inspired by previous studies on cell-penetrating guanidinium-rich transporters and introduced VM conjugates that effectively eradicate Gram-positive biofilm bacteria, persistent cells, and VM-resistant enterococci. They also reported, for the first time, VM conjugates with dendrimer-displayed guanidinium groups exhibiting superior efficacy and breadth. These conjugates, V-r8 and V-R, demonstrated the best activity as single broad-spectrum compounds effective against ESKAPE pathogens. The study introduces a new class of broad-spectrum VM derivatives and outlines a general strategy to enhance or expand antibiotic performance through combined mode-of-action and function-oriented design studies.
|
[
"Silvia Pisani",
"Shafia Tufail",
"Mariella Rosalia",
"Rossella Dorati",
"Ida Genta",
"Enrica Chiesa",
"Bice Conti"
] |
https://doi.org/10.3390/jfb15070194
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
39057315_p56
|
39057315
|
sec[4]/sec[4]/p[0]
|
5.5. Micelle-Based Drug Delivery
| 3.908203 |
biomedical
|
Review
|
[
0.9990234375,
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0.0006089210510253906
] |
[
0.2213134765625,
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0.7734375,
0.0005259513854980469
] |
Micelles are self-assembled, amphiphilic colloidal aggregates that encapsulate hydrophobic drugs, protecting them from degradation and aiding their transport in the body’s aqueous environment. Their properties, such as size, biocompatibility, and controlled release, make them significantly attractive for drug delivery. They can target specific tissues, decrease potential drug toxicity, and allow for sustained and targeted drug delivery. Several studies have shown the potential of micelle-based delivery in overcoming challenges associated with conventional antibiotic administration and specifically with GS and VM.
|
[
"Silvia Pisani",
"Shafia Tufail",
"Mariella Rosalia",
"Rossella Dorati",
"Ida Genta",
"Enrica Chiesa",
"Bice Conti"
] |
https://doi.org/10.3390/jfb15070194
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
39057315_p57
|
39057315
|
sec[4]/sec[4]/p[1]
|
5.5. Micelle-Based Drug Delivery
| 4.136719 |
biomedical
|
Study
|
[
0.99951171875,
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] |
[
0.998046875,
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] |
Xia, W. and colleagues carried out a study intended to create a novel dual-drug delivery system using mesoporous bioactive glass/polypeptide graft copolymer nanomicelle composites. The researchers utilized water-soluble GS and fat-soluble naproxen as models. Each of these drugs was contained within mesoporous bioactive glass and polypeptide nano-micelles, respectively. The release of these drugs was subsequently investigated at various pH levels. The study showed the pH-controlled release of individual drugs. Gentamicin was predominantly released from the mesoporous bioactive glass in an acidic environment, whereas naproxen was rapidly released from the polypeptide nano-micelles in an alkaline environment. This pH-controlled release implies that individual drug release can be influenced by the environmental pH. This case study sheds light on the development of dual-drug delivery systems, showing the potential of mesoporous bioactive glass/polypeptide graft copolymer nano-micelle composites in improving therapeutic efficacy while reducing adverse effects. The pH-controlled release mechanism is a potential technique to target and sustain medication delivery.
|
[
"Silvia Pisani",
"Shafia Tufail",
"Mariella Rosalia",
"Rossella Dorati",
"Ida Genta",
"Enrica Chiesa",
"Bice Conti"
] |
https://doi.org/10.3390/jfb15070194
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999995 |
39057315_p58
|
39057315
|
sec[4]/sec[4]/p[2]
|
5.5. Micelle-Based Drug Delivery
| 4.042969 |
biomedical
|
Study
|
[
0.99951171875,
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] |
[
0.998046875,
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] |
Vancomycin-loaded micelles were discovered to be more efficient than free vancomycin in treating MRSA infections in mice. It has been reported that micelle-encapsulated vancomycin had better targeting and penetration into infected tissues, resulting in higher bacterial death and a lower bacterial load compared to the free drug. Furthermore, the micelle-based formulation showed lower systemic exposure, potentially reducing the likelihood of adverse effects.
|
[
"Silvia Pisani",
"Shafia Tufail",
"Mariella Rosalia",
"Rossella Dorati",
"Ida Genta",
"Enrica Chiesa",
"Bice Conti"
] |
https://doi.org/10.3390/jfb15070194
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
39057315_p59
|
39057315
|
sec[4]/sec[4]/p[3]
|
5.5. Micelle-Based Drug Delivery
| 4.472656 |
biomedical
|
Study
|
[
0.9990234375,
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[
0.970703125,
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Chen, M. and colleagues used, as a base material for micelle carrier preparation, amphiphilic poly(ethylene glycol)-poly(ε-caprolactone) (PECL) copolymers conjugated with VM as targeting ligands via pH-cleavable hydrazone bonds (VM-hyd-PECL). Then, ciprofloxacin (CIP) was encapsulated to produce VM-hyd-PECL/Cip micelles showing an average size of 77 nm and CIP loading of 4.5%. The poly(ethylene glycol) shells and the expansion of VM moieties on the micelle surface were intended to improve blood circulation and bacterial recognition. The study found that deshielding VM shells in an acidic environment disturbs the hydrophobic/hydrophilic equilibrium, resulting in increased micelle sizes. This allows lipase to degrade poly(ε-caprolactone) near the infection site, releasing encapsulated CIP for bacterial destruction. Micelle treatment increased the survival rate of Pseudomonas aeruginosa-infected mice while decreasing bacterial burdens and alveolar damage in the lungs when compared to free drugs and micelles without VM moiety inoculation. Three doses of VM-hyd-PECL/Cip micelles improved animal survival, reduced bacterial colonization in the lungs, and nearly restored the normal alveolar microstructure. This case study illustrates an approach for improving bacterial targeting of micelles using an antibiotic (VM) and sequentially triggering the release of antibiotics (VM and CIP) at the infection site. These case studies highlight the potential of micelle-based delivery systems to overcome limitations associated with conventional antibiotic administration. By improving the solubility, bioavailability, and targeting, micelles offer a promising system for enhancing the efficacy and safety of antibiotics in the fight against bacterial infections, including those caused by MDR bacteria.
|
[
"Silvia Pisani",
"Shafia Tufail",
"Mariella Rosalia",
"Rossella Dorati",
"Ida Genta",
"Enrica Chiesa",
"Bice Conti"
] |
https://doi.org/10.3390/jfb15070194
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
39057315_p60
|
39057315
|
sec[4]/sec[4]/p[4]
|
5.5. Micelle-Based Drug Delivery
| 3.876953 |
biomedical
|
Review
|
[
0.99853515625,
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[
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However, further research is required to explore the long-term safety and efficacy of micelle-based drug delivery systems and translate these promising preclinical findings into clinical applications. Future investigations should focus on optimizing the micelle design, conducting large-scale clinical trials, and addressing regulatory considerations to ensure the safe and effective translation of this technology into clinical practice.
|
[
"Silvia Pisani",
"Shafia Tufail",
"Mariella Rosalia",
"Rossella Dorati",
"Ida Genta",
"Enrica Chiesa",
"Bice Conti"
] |
https://doi.org/10.3390/jfb15070194
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999995 |
39057315_p61
|
39057315
|
sec[4]/sec[5]/p[0]
|
5.6. Carbon-Nanotube (CNT)-Based Drug Delivery
| 3.957031 |
biomedical
|
Review
|
[
0.99755859375,
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[
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This section addresses the suitability of CNTs for delivering antibiotics and their potential benefits in overcoming challenges associated with conventional antibiotic administration. Carbon nanotubes are cylindrical nanostructures formed by rolling a single sheet of graphene into a seamless tube. They possess a high aspect ratio, exceptional strength, stability, tailorable functionality, and unique electrical properties. These attributes make them suitable for various applications, including drug loading, targeted drug delivery, and triggered drug release .
|
[
"Silvia Pisani",
"Shafia Tufail",
"Mariella Rosalia",
"Rossella Dorati",
"Ida Genta",
"Enrica Chiesa",
"Bice Conti"
] |
https://doi.org/10.3390/jfb15070194
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999995 |
39057315_p62
|
39057315
|
sec[4]/sec[5]/p[1]
|
5.6. Carbon-Nanotube (CNT)-Based Drug Delivery
| 4.078125 |
biomedical
|
Study
|
[
0.99951171875,
0.00018775463104248047,
0.00015413761138916016
] |
[
0.99853515625,
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0.00006568431854248047
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Liu, C. and colleagues aimed to overcome the limitations of multi-walled carbon nanotubes (MWCNTs) in infection resistance due to aggregation into the polymer matrix and weak bactericidal properties. The researchers created VM-hydrochloride-modified MWCNT (VM-MWCNT) by reacting the carboxyl group of MWCNT with VM’s amide group. The Van-MWCNT was absorbed onto TPU electrospun nanofibers (TPU/Van-MWCNT) via ultrasonication. The preparation technique was non-toxic and utilized water as a green solvent. The approach successfully minimized the aggregation of VM-MWCNT into electrospun nanofibers. The study found that VM-MWCNT has a lower minimum inhibitory concentration (MIC) against S. aureus compared to MWCNT. The TPU/Van-MWCNT showed remarkable antibacterial characteristics, indicating possible uses in wound dressings.
|
[
"Silvia Pisani",
"Shafia Tufail",
"Mariella Rosalia",
"Rossella Dorati",
"Ida Genta",
"Enrica Chiesa",
"Bice Conti"
] |
https://doi.org/10.3390/jfb15070194
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
39057315_p63
|
39057315
|
sec[4]/sec[5]/p[2]
|
5.6. Carbon-Nanotube (CNT)-Based Drug Delivery
| 4.09375 |
biomedical
|
Study
|
[
0.99951171875,
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] |
[
0.9990234375,
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Al Thaher and colleagues studied a novel PMMA bone cement to prevent prosthetic joint infections (PJIs). The goal was to investigate GS release from carbon nanotubes (CNTs) embedded in polymethyl methacrylate (PMMA) used as bone cement over several weeks to provide post-surgery prophylaxis against PJIs. Gentamicin was examined at various CNT concentrations, either as a powder or preloaded on carboxyl functionalized CNTs. The findings revealed that CNT-loaded bone cements released gentamicin for several weeks longer than GS-containing bone cement. Furthermore, the addition of CNT increased the amount of GS released without impairing the nanocomposite’s mechanical and antibacterial properties. The bone cement implemented with CNT performed similarly to the corresponding powder-containing cement in terms of cytotoxicity. This novel technique could be effective in preventing PJIs in orthopedic procedures.
|
[
"Silvia Pisani",
"Shafia Tufail",
"Mariella Rosalia",
"Rossella Dorati",
"Ida Genta",
"Enrica Chiesa",
"Bice Conti"
] |
https://doi.org/10.3390/jfb15070194
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
39057315_p64
|
39057315
|
sec[5]/p[0]
|
6. Nanosized DDS Interactions with Bacterial Membranes
| 3.90625 |
biomedical
|
Study
|
[
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[
0.85888671875,
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] |
As reported in the examples above, nanosized DDSs have been an area of significant research interest due to their potential to improve the efficacy and specificity of antimicrobial treatments. However, the mechanism of interaction of these nanosized DDSs with bacterial membranes still remains a critical aspect to explain their function. The main mechanisms involved the interaction between DDS and bacterial membranes are electrostatic interactions, hydrophobic interactions, and ligand–receptor binding .
|
[
"Silvia Pisani",
"Shafia Tufail",
"Mariella Rosalia",
"Rossella Dorati",
"Ida Genta",
"Enrica Chiesa",
"Bice Conti"
] |
https://doi.org/10.3390/jfb15070194
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999995 |
39057315_p65
|
39057315
|
sec[5]/p[1]
|
6. Nanosized DDS Interactions with Bacterial Membranes
| 3.728516 |
biomedical
|
Other
|
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Gram-negative bacterial membranes, due to the presence of phospholipids and lipopolysaccharides (LPS), express a negative charge; exploiting electrostatic interaction mechanisms can be used to design DDSs with positive charges to enhance electrostatic attraction, improving adhesion and interactions with bacterial membranes .
|
[
"Silvia Pisani",
"Shafia Tufail",
"Mariella Rosalia",
"Rossella Dorati",
"Ida Genta",
"Enrica Chiesa",
"Bice Conti"
] |
https://doi.org/10.3390/jfb15070194
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
39057315_p66
|
39057315
|
sec[5]/p[2]
|
6. Nanosized DDS Interactions with Bacterial Membranes
| 4.160156 |
biomedical
|
Study
|
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0.0003457069396972656
] |
Bacterial membranes are composed of a lipid bilayer that has hydrophobic regions. DDSs with hydrophobic surfaces or hydrophobic drug molecules can integrate more effectively into these regions, facilitating drug delivery. Moreover, is important to also consider the differences in compositions and structures of Gram-positive and Gram-negative membranes. The wall of Gram-positive bacteria consists of a thick peptidoglycan layer (20–80 nm), and unlike Gram-negative bacteria, Gram-positive bacteria do not have an outer membrane. Gram-negative bacteria have an outer membrane composed of lipopolysaccharide (LPS), phospholipids, and proteins, with a thinner peptidoglycan layer (2–7 nm) located in the periplasmic space between the inner and outer membranes .
|
[
"Silvia Pisani",
"Shafia Tufail",
"Mariella Rosalia",
"Rossella Dorati",
"Ida Genta",
"Enrica Chiesa",
"Bice Conti"
] |
https://doi.org/10.3390/jfb15070194
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
39057315_p67
|
39057315
|
sec[5]/p[3]
|
6. Nanosized DDS Interactions with Bacterial Membranes
| 4.183594 |
biomedical
|
Study
|
[
0.99951171875,
0.00028514862060546875,
0.00019407272338867188
] |
[
0.96484375,
0.0190277099609375,
0.015869140625,
0.0003533363342285156
] |
Finally, for a more specific and selective interaction, DDSs can be functionalized with ligands that can bind receptors on bacterial surfaces (e.g., antibodies, peptides, sugars) enhancing targeting and uptake. In the case of Gram-positive targeting, functionalizing DDSs with molecules that can interact with teichoic and lipoteichoic acids can enhance adherence and uptake. For Gram-negative bacteria, a strategy to overcome the limiting step of a thicker membrane could be design-engineered DDSs to utilize porins or interact with LPS for entry or to disrupt the outer membrane to gain access to the periplasmic space .
|
[
"Silvia Pisani",
"Shafia Tufail",
"Mariella Rosalia",
"Rossella Dorati",
"Ida Genta",
"Enrica Chiesa",
"Bice Conti"
] |
https://doi.org/10.3390/jfb15070194
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
39057315_p68
|
39057315
|
sec[5]/p[4]
|
6. Nanosized DDS Interactions with Bacterial Membranes
| 2.931641 |
biomedical
|
Study
|
[
0.998046875,
0.0003466606140136719,
0.001628875732421875
] |
[
0.8056640625,
0.182373046875,
0.01092529296875,
0.0009655952453613281
] |
Figure 6 summarizes nanosized DDS interactions with bacterial membranes (Gram-positive and Gram-negative).
|
[
"Silvia Pisani",
"Shafia Tufail",
"Mariella Rosalia",
"Rossella Dorati",
"Ida Genta",
"Enrica Chiesa",
"Bice Conti"
] |
https://doi.org/10.3390/jfb15070194
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
39057315_p69
|
39057315
|
sec[6]/p[0]
|
7. Discussion
| 4.226563 |
biomedical
|
Review
|
[
0.98583984375,
0.007572174072265625,
0.006465911865234375
] |
[
0.007007598876953125,
0.0009737014770507812,
0.9912109375,
0.000583648681640625
] |
Nanoparticle-based drug delivery systems provide attractive alternatives for improving treatment efficacy, overcoming resistance, and limiting the unwanted effects of antibiotics. In this comprehensive review, we explored various nanosystems for GS and VM delivery. Polymeric NPs are extensively studied because of their biocompatibility, configurable characteristics, and sustained release profiles. For GS and VM the most studied polymer NPs are poly(lactic-co-glycolic acid) (PLGA). It provides the advantages of high drug-loading capacity, controlled release, and enhanced antibacterial activity . In the case of inorganic nanoparticles, silver nanoparticles (AgNPs) and gold nanoparticles (AuNPs) are extensively studied for GS and VM. They offer the advantage of greater antibacterial activity suitable drug loading and stability . Liposomes, lipid-based vesicles, are versatile drug carriers providing the advantages of the improved bioavailability, controlled release, and high drug-loading capacity that has been widely exploited for GS and VM. There exists a variation in drug-encapsulating efficiency for both antibiotics depending the type of liposomes and the experimental parameters. For instance, the encapsulation efficiency for gentamicin was reported to be 25.7 ± 1.0% for DPPC/chol vesicles , 2.9% for neutral, DPPC-Chol (55:45), 9.3% for anionic DOPE–N-succinyl-DOPE–PEG (69:30:1) , 1.8% to 43.6% (1.8% ± 0.15% for neutral liposomes, 37.2% ± 0.46% and 43.6% ± 0.65% for negatively charged liposomes) , and 4.51 ± 0.54% for neutral liposomes (DMPC-Chol 2:1) . For VM, the encapsulation efficiency also varies as it was 8.84 ± 2.1% for neutral liposomes , 9 ± 2% (neutral) and 12 ± 3% (PEGylated) , 78.66% (containing propylene glycol as a permeation enhancer) , and 9% (for DCP) and 20% (for DMPG) . Dendrimers also offer advantages of tailored surface properties, but their toxicity needs to be studied well. Among them, PMAM dendrimers are most commonly used. Micelles also improve drug solubility and stability with controlled release. Carbon nanotubes offers unique physiochemical properties, but their toxicity needs to be considered as well.
|
[
"Silvia Pisani",
"Shafia Tufail",
"Mariella Rosalia",
"Rossella Dorati",
"Ida Genta",
"Enrica Chiesa",
"Bice Conti"
] |
https://doi.org/10.3390/jfb15070194
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
39057315_p70
|
39057315
|
sec[6]/p[1]
|
7. Discussion
| 3.896484 |
biomedical
|
Study
|
[
0.99951171875,
0.00019598007202148438,
0.0003521442413330078
] |
[
0.71826171875,
0.009918212890625,
0.271240234375,
0.0004189014434814453
] |
Although, PLGA NPs, AgNPs, liposomes, PAMAM dendrimers, polymeric micelles, and functionalized CNTs are potential nanosystems for GS and VM administration, liposomes stand out for their high drug loading, controlled release, and increased bioavailability, also due to their ability to cross bacterial membranes via fusion with them. Liposomes show strong efficacy against bacterial biofilms (due to their structure, they reach deeper biofilm layers), and also the concern of toxicity is very less for liposomes. To the best of our knowledge, there are no drug products on the market made from liposomal GS or VM, while there are, in the market, drug products made from liposomes loaded with amikacin and tobramycin. These findings mean that liposomal formulations loaded with GS and VM still need to be optimized.
|
[
"Silvia Pisani",
"Shafia Tufail",
"Mariella Rosalia",
"Rossella Dorati",
"Ida Genta",
"Enrica Chiesa",
"Bice Conti"
] |
https://doi.org/10.3390/jfb15070194
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
39057315_p71
|
39057315
|
sec[6]/p[2]
|
7. Discussion
| 3.960938 |
biomedical
|
Review
|
[
0.9990234375,
0.0003879070281982422,
0.0007791519165039062
] |
[
0.292236328125,
0.1243896484375,
0.58251953125,
0.0008554458618164062
] |
From an industrial standpoint, liposomes are one of the most commonly employed nanodrug delivery technologies. They have been widely researched and are currently employed for various drugs that are approved by the FDA. This is because they are biocompatible, can encapsulate both hydrophilic and hydrophobic medicines, and are easy to produce on a large scale. Liposomes can be made utilizing a variety of processes, including thin-film hydration, reverse-phase evaporation, and detergent removal, which are easily scaled up for industrial manufacturing. However, it is vital to note that the choice of nanodrug delivery system can rely on several aspects, including the nature of the drug, the targeted delivery site, and the specific patient need .
|
[
"Silvia Pisani",
"Shafia Tufail",
"Mariella Rosalia",
"Rossella Dorati",
"Ida Genta",
"Enrica Chiesa",
"Bice Conti"
] |
https://doi.org/10.3390/jfb15070194
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
39057315_p72
|
39057315
|
sec[6]/p[3]
|
7. Discussion
| 3.992188 |
biomedical
|
Review
|
[
0.998046875,
0.00103759765625,
0.0009427070617675781
] |
[
0.05950927734375,
0.023651123046875,
0.916015625,
0.0006051063537597656
] |
Challenges and future directions in nanoparticle-based drug delivery systems concern the development of cost-effective and scalable manufacturing processes for antibiotic-loaded nanoparticles. With a view to clinical application, ensuring the stability of nanoparticles during storage and transportation is critical. Eventually, from a regulatory point of view, comprehensive studies on the long-term safety and potential immunogenicity of nanoparticle systems are required. When deciding on the best solution, researchers should examine both safety profiles and particular application requirements. Future advances in nanoparticle–drug conjugates provide considerable promise for addressing antibiotic resistance.
|
[
"Silvia Pisani",
"Shafia Tufail",
"Mariella Rosalia",
"Rossella Dorati",
"Ida Genta",
"Enrica Chiesa",
"Bice Conti"
] |
https://doi.org/10.3390/jfb15070194
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999999 |
39057315_p73
|
39057315
|
sec[7]/p[0]
|
8. Conclusions
| 3.923828 |
biomedical
|
Review
|
[
0.99853515625,
0.0007944107055664062,
0.0005598068237304688
] |
[
0.18603515625,
0.142333984375,
0.67041015625,
0.0013275146484375
] |
The growing burden of infectious diseases, along with increasing pathogen resistance to current therapeutic therapies, necessitates novel drug delivery techniques. Nanoparticles’ unique physicochemical features provide a viable solution with respect to standard drug formulation limits, by increasing bioavailability, facilitating drug-controlled release, and permitting targeted administration. This not only maximizes therapeutic efficacy but also reduces the likelihood of resistance development.
|
[
"Silvia Pisani",
"Shafia Tufail",
"Mariella Rosalia",
"Rossella Dorati",
"Ida Genta",
"Enrica Chiesa",
"Bice Conti"
] |
https://doi.org/10.3390/jfb15070194
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
39057315_p74
|
39057315
|
sec[7]/p[1]
|
8. Conclusions
| 3.808594 |
biomedical
|
Review
|
[
0.99755859375,
0.0012121200561523438,
0.001399993896484375
] |
[
0.0194091796875,
0.21240234375,
0.76708984375,
0.0011463165283203125
] |
However, the journey to successful nanodrug delivery systems is filled with obstacles, ranging from the intricacies of microbial resistance to the difficulties posed by biofilm-associated and intracellular infections. Nevertheless, the nanosized systems still need optimization as far as their manufacturing technique and drug loading is concerned. Some measures that can complement the use of nanosized drug delivery devices include enhanced diagnostics, judicious antibiotic use, novel antibiotics discovery, and combination therapy.
|
[
"Silvia Pisani",
"Shafia Tufail",
"Mariella Rosalia",
"Rossella Dorati",
"Ida Genta",
"Enrica Chiesa",
"Bice Conti"
] |
https://doi.org/10.3390/jfb15070194
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
39057315_p75
|
39057315
|
sec[7]/p[2]
|
8. Conclusions
| 3.738281 |
biomedical
|
Other
|
[
0.99609375,
0.00234222412109375,
0.0016546249389648438
] |
[
0.01329803466796875,
0.5078125,
0.47705078125,
0.0017652511596679688
] |
In conclusion, while the road ahead is challenging, the potential of nanosized drug delivery devices to improve the efficacy of antibiotics, such as gentamicin and vancomycin, is promising. Continued research and development in this subject are critical to realize its promise and reverse the tide in the ever-changing war against infectious diseases. The goal is to create a synergistic platform that targets a wide spectrum of infectious risks, ultimately improving patient outcomes and changing the future of healthcare.
|
[
"Silvia Pisani",
"Shafia Tufail",
"Mariella Rosalia",
"Rossella Dorati",
"Ida Genta",
"Enrica Chiesa",
"Bice Conti"
] |
https://doi.org/10.3390/jfb15070194
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277919_p0
|
PMC11277919
|
sec[0]/p[0]
|
1. Introduction
| 3.933594 |
biomedical
|
Study
|
[
0.99951171875,
0.0003674030303955078,
0.0002658367156982422
] |
[
0.53662109375,
0.01197052001953125,
0.450927734375,
0.0007815361022949219
] |
Pancreatic neuroendocrine neoplasms (pNENs) rank as the third most common neuroendocrine tumor subtype in the gastro-entero-pancreatic system . The incidence presents a steady rise over the last few decades worldwide, with a five-year survival of 37.6% . However, even in the pathologically well-differentiated tumors, the high heterogeneity of pNENs exhibits distinct biological behavior that affects the treatment decision and patient prognosis.
|
[
"Li Yu",
"Mengfei Fu",
"Liu Yang",
"Hui Sun"
] |
https://doi.org/10.3390/jpm14070760
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277919_p1
|
PMC11277919
|
sec[0]/p[1]
|
1. Introduction
| 3.804688 |
biomedical
|
Review
|
[
0.99658203125,
0.0015707015991210938,
0.0018320083618164062
] |
[
0.060516357421875,
0.12890625,
0.8095703125,
0.001049041748046875
] |
The classifications of pNENs according to the histological grade and the staging by American Joint Committee on Cancer (AJCC) have been widely applied in clinical practice . These indices offer guidance on the course of treatment as well as insights into the patient prognosis. However, the AJCC staging system is based on the imaging examination, which is costly and often diagnosed pNENs occasionally when adopted for other diseases. Additionally, the prognostic value of this staging system is limited for patients without metastasis.
|
[
"Li Yu",
"Mengfei Fu",
"Liu Yang",
"Hui Sun"
] |
https://doi.org/10.3390/jpm14070760
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11277919_p2
|
PMC11277919
|
sec[0]/p[2]
|
1. Introduction
| 3.982422 |
biomedical
|
Study
|
[
0.99951171875,
0.00014591217041015625,
0.0002065896987915039
] |
[
0.9921875,
0.0014781951904296875,
0.006221771240234375,
0.00011914968490600586
] |
Laboratory tests are generally inexpensive and easily acquirable in clinic. Nonetheless, the prognostic value of hematological indices is frequently underestimated, particularly for those that appear to have no direct correlation with tumor behaviors. For instance, blood serum levels of alkaline phosphatase (ALP) and albumin (Alb) are not tumor biomarkers, but their ratio (ALP to Alb ratio, APAR) can be useful in predicting a patients’ prognosis for a variety of cancer types . However, a previous study indicated that the APAR is insufficient to predict the overall survival (OS) of pNENs . Therefore, it is imperative to explore more reliable indicators for these patients.
|
[
"Li Yu",
"Mengfei Fu",
"Liu Yang",
"Hui Sun"
] |
https://doi.org/10.3390/jpm14070760
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277919_p3
|
PMC11277919
|
sec[0]/p[3]
|
1. Introduction
| 3.800781 |
biomedical
|
Study
|
[
0.9990234375,
0.00028228759765625,
0.0005927085876464844
] |
[
0.58984375,
0.0035686492919921875,
0.40625,
0.00046181678771972656
] |
Recent studies have suggested that hyperglycemia may contribute to the cancer progression, though no substantial evidence indicates the possible link among them . The prediction value of fasting blood glucose (FBG) for cancer patients is still under investigation due to the rarely relevant study. Additionally, the nutrition and inflammatory status of patients are linked to their outcomes. Some studies reported that the high C-reactive protein (CRP), low albumin, and low hemoglobin showed an increased risk trend of negative prognosis, but there are no significant differences . These findings indicated that a single indicator is insufficient to predict the patients’ outcome.
|
[
"Li Yu",
"Mengfei Fu",
"Liu Yang",
"Hui Sun"
] |
https://doi.org/10.3390/jpm14070760
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277919_p4
|
PMC11277919
|
sec[0]/p[4]
|
1. Introduction
| 3.660156 |
biomedical
|
Study
|
[
0.9990234375,
0.00041866302490234375,
0.0004906654357910156
] |
[
0.9990234375,
0.0005106925964355469,
0.00018835067749023438,
0.00008249282836914062
] |
Given these limitations, we conducted the present study to explore the value of three novel indicators, which are the FBG-to-albumin ratio (FAR), FBG-to-lymphocytes ratio (FLR), and FBG-to-hemoglobin ratio (FHR), for predicting the prognosis of pNEN patients and detecting their synchronous metastasis. As far as we know, there are no reports about these three indicators.
|
[
"Li Yu",
"Mengfei Fu",
"Liu Yang",
"Hui Sun"
] |
https://doi.org/10.3390/jpm14070760
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11277919_p5
|
PMC11277919
|
sec[1]/sec[0]/p[0]
|
2.1. Patient Selection
| 3.287109 |
biomedical
|
Study
|
[
0.95361328125,
0.0455322265625,
0.0007658004760742188
] |
[
0.98486328125,
0.0105438232421875,
0.0010499954223632812,
0.0036106109619140625
] |
Consecutive patients who underwent surgical resection and were pathologically diagnosed with pNEN at our center from 1 May 2010 to 31 December 2021 were reviewed. The exclusion criteria were as follows: patients who (a) are previously diagnosed with other malignant tumors; (b) complicated with serious comorbidities, such as severe dysfunction of the liver, kidney or heart; and (c) have missing data.
|
[
"Li Yu",
"Mengfei Fu",
"Liu Yang",
"Hui Sun"
] |
https://doi.org/10.3390/jpm14070760
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11277919_p6
|
PMC11277919
|
sec[1]/sec[0]/p[1]
|
2.1. Patient Selection
| 4.058594 |
biomedical
|
Study
|
[
0.998046875,
0.001708984375,
0.00017714500427246094
] |
[
0.99853515625,
0.0006728172302246094,
0.000499725341796875,
0.00021088123321533203
] |
The demographic, clinical, laboratory, imaging, and pathological data of included patients were collected from our hospital medical record system. The histological grade was defined by the Ki-67 index and mitotic rate according to the 2019 World Health Organization (WHO) classification of endocrine organ tumors. The TNM stages were defined according to the 8th version of classification system by the AJCC. Functional tumors are defined as having particular symptoms and signs associated with hormone excess, such as insulinoma (hyperinsulinemia) and glucagonoma (hyperglycemia), etc. One lesion was defined as single, and the tumor number ≥2 was defined as multiple.
|
[
"Li Yu",
"Mengfei Fu",
"Liu Yang",
"Hui Sun"
] |
https://doi.org/10.3390/jpm14070760
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277919_p7
|
PMC11277919
|
sec[1]/sec[1]/p[0]
|
2.2. Follow-Up
| 3.802734 |
biomedical
|
Study
|
[
0.78857421875,
0.2098388671875,
0.0016107559204101562
] |
[
0.81689453125,
0.170166015625,
0.002590179443359375,
0.01019287109375
] |
The follow-up was conducted by telephone or outpatient visit with a deadline of 30 June 2022. The treatment efficacy was evaluated based on their imaging examination of computed tomography or magnetic resonance imaging. Progression-free survival (PFS) was defined as the duration from the first surgery procedure to the date of tumor progression confirmed radiologically. Overall survival (OS) was defined as the duration from the first surgery procedure to the death or the last follow-up.
|
[
"Li Yu",
"Mengfei Fu",
"Liu Yang",
"Hui Sun"
] |
https://doi.org/10.3390/jpm14070760
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999995 |
PMC11277919_p8
|
PMC11277919
|
sec[1]/sec[2]/p[0]
|
2.3. Statistical Analysis
| 4.019531 |
biomedical
|
Study
|
[
0.99951171875,
0.0003039836883544922,
0.00021600723266601562
] |
[
0.9990234375,
0.000431060791015625,
0.0005159378051757812,
0.00007331371307373047
] |
All statistical analyses were conducted by SPSS (version 26.0) and Graph-Pad Prism (version 8.0) software. Continuous variables were presented as mean ± standard deviation (SD), and differences between groups were analyzed using t -test between two groups and ANOVA analysis among three groups (including the comparison among any two groups). The categorical variables were expressed as frequencies and percentages, and the differences were analyzed by the Chi-square test. Uni-and multivariable Cox proportional hazard regression models were performed to explore the effects of several prognostic factors. The cross-validation was conducted using bootstrap method to demonstrate the predictive ability of FBG-based predictors . Variables with p < 0.05 in univariate analysis were entered into the multivariate analysis. The time-dependent receiver operating characteristic (ROC) curves were plotted and the Youden indices were calculated to determine optimal cutoff value. The Kaplan–Meier method was used to estimate the survival curve which was compared by the log-rank test. A two-tailed p < 0.05 was considered to be statistically significant.
|
[
"Li Yu",
"Mengfei Fu",
"Liu Yang",
"Hui Sun"
] |
https://doi.org/10.3390/jpm14070760
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277919_p9
|
PMC11277919
|
sec[2]/sec[0]/p[0]
|
3.1. Baseline Characteristics
| 4.023438 |
biomedical
|
Study
|
[
0.99072265625,
0.009002685546875,
0.00037288665771484375
] |
[
0.99755859375,
0.0014209747314453125,
0.00038886070251464844,
0.0006895065307617188
] |
A total of 187 pNEN patients underwent surgical resection were reviewed, and there were 178 patients eligible for further analyses . The whole cohort comprised 83 (46.6%) males and 95 (53.4%) females, with a mean age of 48.1 ± 13.5 years. The symptoms of hypoglycemia (palpitation, excessive perspiration, tremor, and starvation, etc., n = 58), abdominal bloating (n = 6), and diarrhea (n = 2), etc., were observed in patients with a functional tumor. There were 98 (55.1%), 68 (38.2%), and 12 (6.7%) patients at the histological grade of G1, G2, and G3, respectively, and 134 (75.3%), 17 (9.6%), 6 (3.4%), and 21 (11.8%) patients at the AJCC stages of I, II, III, and IV, respectively. The baseline characteristics of the included patients were summarized in Table 1 .
|
[
"Li Yu",
"Mengfei Fu",
"Liu Yang",
"Hui Sun"
] |
https://doi.org/10.3390/jpm14070760
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11277919_p10
|
PMC11277919
|
sec[2]/sec[1]/p[0]
|
3.2. Cutoff Values of Fasting Blood Glucose-Based Novel Indexes
| 4.105469 |
biomedical
|
Study
|
[
0.9990234375,
0.0004372596740722656,
0.0003223419189453125
] |
[
0.99951171875,
0.00021183490753173828,
0.0003733634948730469,
0.00005793571472167969
] |
ROC curves were generated to determine the value of FAR, FLR, and FHR for prediction. As for PFS , the area under the curve (AUC) was 0.693 for FAR, 0.690 for FLR, and 0.661 for FHR, respectively. The optimal cutoff value was 0.17 for FAR, 2.85 for FLR, and 0.028 for FHR, respectively. To further assess the predictive efficacy of these cutoff values for OS, ROC curves were also established . The results showed that the AUC was 0.770, 0.692, and 0.715 for FAR, FLR, and FHR, respectively. Additionally, the APAR was also incorporated. To confirm the reliability of these results, the cross-validation was conducted by bootstrap. The bootstrap performances were echoed with the above results. The optimal cutoff value of APAR was 2.2, the AUC was 0.730 for PFS and 0.725 for OS, respectively.
|
[
"Li Yu",
"Mengfei Fu",
"Liu Yang",
"Hui Sun"
] |
https://doi.org/10.3390/jpm14070760
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999999 |
PMC11277919_p11
|
PMC11277919
|
sec[2]/sec[2]/p[0]
|
3.3. Prediction Roles of Fasting Blood Glucose-Based Indexes for PFS
| 4.097656 |
biomedical
|
Study
|
[
0.9990234375,
0.000640869140625,
0.00028896331787109375
] |
[
0.99951171875,
0.00023448467254638672,
0.000278472900390625,
0.00006586313247680664
] |
Subgroup analyses were conducted to evaluate the value of FAR, FLR, and FHR in predicting PFS among the above resected groups. As shown in Figure 3 , the PFS (median PFS was not applicable) in the low-FAR group (<0.17) was significantly longer than the higher value group (median, 60.0 ± 19.1 months) ( p < 0.001). The low-FLR group (<2.85) was associated with significantly better PFS compared with the higher value group ( p < 0.001). Additionally, the PFS in the low-FHR group (<0.028) was also significantly prolonged compared with the high-FHR group ( p = 0.002).
|
[
"Li Yu",
"Mengfei Fu",
"Liu Yang",
"Hui Sun"
] |
https://doi.org/10.3390/jpm14070760
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11277919_p12
|
PMC11277919
|
sec[2]/sec[3]/p[0]
|
3.4. Risk Factors of PFS for pNEN Patients
| 4.105469 |
biomedical
|
Study
|
[
0.9990234375,
0.0005974769592285156,
0.00021469593048095703
] |
[
0.9990234375,
0.00025844573974609375,
0.0003981590270996094,
0.00009202957153320312
] |
Univariate and multivariate analyses were performed to determine the risk factors of PFS for pNEN patients . The results of univariate analysis showed that the FAR ( p < 0.001), FLR ( p < 0.001), FHR ( p = 0.003), APAR ( p < 0.001), albumin ( p = 0.008), FBG, AJCC stage ( p < 0.001), histological grade ( p = 0.002), and tumor diameter ( p = 0.048) were significantly associated with PFS. The results of multivariate analysis demonstrated that the FLR (hazard ratio (HR), 3.74; 95% confidence interval (CI), 1.09, 12.81; p = 0.035), APAR (HR, 0.19; 95% CI: 0.85, 0.97; p = 0.021), albumin (HR, 0.91; 95% CI: 0.85, 0.97; p = 0.004), and AJCC stage (HR, 11.97; 95% CI: 3.31, 43.30; p < 0.001) were independent predictors of PFS for pNEN patients.
|
[
"Li Yu",
"Mengfei Fu",
"Liu Yang",
"Hui Sun"
] |
https://doi.org/10.3390/jpm14070760
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999995 |
PMC11277919_p13
|
PMC11277919
|
sec[2]/sec[4]/p[0]
|
3.5. Prediction Roles of Fasting Blood Glucose-Based Indexes for OS
| 4.054688 |
biomedical
|
Study
|
[
0.9990234375,
0.0006198883056640625,
0.0005097389221191406
] |
[
0.99951171875,
0.0002684593200683594,
0.000255584716796875,
0.000059664249420166016
] |
As shown in Figure 5 , the low-FAR was related to significantly better OS than the higher value group ( p < 0.001). The OS was significantly prolonged in the low-FLR group compared with the high-FLR group ( p = 0.037). Additionally, the low-FHR group also showed significantly longer OS than the higher value group ( p = 0.024).
|
[
"Li Yu",
"Mengfei Fu",
"Liu Yang",
"Hui Sun"
] |
https://doi.org/10.3390/jpm14070760
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277919_p14
|
PMC11277919
|
sec[2]/sec[5]/p[0]
|
3.6. Risk Factors of OS for pNEN Patients
| 4.097656 |
biomedical
|
Study
|
[
0.9990234375,
0.0005884170532226562,
0.00023257732391357422
] |
[
0.99951171875,
0.0002529621124267578,
0.00034999847412109375,
0.0000870823860168457
] |
The results of univariate analyses presented that the FAR ( p < 0.001), APAR ( p = 0.011), albumin ( p = 0.008), FBG ( p < 0.001), AJCC stage ( p = 0.003), and histological grade ( p = 0.036) were independent predictors of OS for pNEN patients. Further multivariate analyses showed that the FAR (HR, 7.02; 95% CI: 1.74, 28.37; p = 0.006) and albumin (HR, 0.89; 95% CI: 0.81, 0.99; p = 0.023) were independent predictors of OS.
|
[
"Li Yu",
"Mengfei Fu",
"Liu Yang",
"Hui Sun"
] |
https://doi.org/10.3390/jpm14070760
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11277919_p15
|
PMC11277919
|
sec[2]/sec[6]/p[0]
|
3.7. Baseline Characteristics and Risk Factors of PFS for Patients with pNEN and Metastasis
| 2.130859 |
biomedical
|
Study
|
[
0.98974609375,
0.00830841064453125,
0.0018053054809570312
] |
[
0.982421875,
0.01385498046875,
0.0010805130004882812,
0.0025577545166015625
] |
A total of 30 pNEN patients were concurrent with metastasis, and their demographic characteristics were summarized in Table 2 .
|
[
"Li Yu",
"Mengfei Fu",
"Liu Yang",
"Hui Sun"
] |
https://doi.org/10.3390/jpm14070760
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11277919_p16
|
PMC11277919
|
sec[2]/sec[6]/p[1]
|
3.7. Baseline Characteristics and Risk Factors of PFS for Patients with pNEN and Metastasis
| 4.101563 |
biomedical
|
Study
|
[
0.9990234375,
0.0006093978881835938,
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] |
[
0.99951171875,
0.00027108192443847656,
0.0002682209014892578,
0.0000820159912109375
] |
The results of univariate analysis of PFS ( Table 3 ) showed that the FAR was the single independent predictor of patients with pNEN and metastasis (HR, 3.34; 95% CI: 1.11, 10.06; p = 0.032), and the FBG was the predictor of OS ( Table 4 ) for these patients (HR, 1.15; 95% CI: 1.03, 1.28; p = 0.012).
|
[
"Li Yu",
"Mengfei Fu",
"Liu Yang",
"Hui Sun"
] |
https://doi.org/10.3390/jpm14070760
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999995 |
PMC11277919_p17
|
PMC11277919
|
sec[2]/sec[7]/p[0]
|
3.8. Prediction Role of FAR for Patients with pNEN and Metastasis
| 4.101563 |
biomedical
|
Study
|
[
0.9990234375,
0.0005593299865722656,
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] |
[
0.99951171875,
0.0002694129943847656,
0.0002715587615966797,
0.00007408857345581055
] |
As for distinguishing the synchronous metastasis in pNEN patients, the ROC curve showed that the AUC was 0.704 . The low-FAR group was correlated with significantly better PFS compared with the higher-value group ( p = 0.022). Moreover, the lower-value cohort (median, not applicable) also presented significantly prolonged OS when compared with the high-FAR group (median, 60.0 ± 25.1 months) ( p = 0.002).
|
[
"Li Yu",
"Mengfei Fu",
"Liu Yang",
"Hui Sun"
] |
https://doi.org/10.3390/jpm14070760
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277919_p18
|
PMC11277919
|
sec[3]/p[0]
|
4. Discussion
| 4.074219 |
biomedical
|
Study
|
[
0.99951171875,
0.0002741813659667969,
0.00021183490753173828
] |
[
0.99951171875,
0.00017774105072021484,
0.0003719329833984375,
0.00006198883056640625
] |
The highly heterogeneous prognosis of pNEN patients indicates that risk assessment and the development of new reliable indicators are particularly required . Blood markers are regularly measured and easily accessible, which has attracted growing interest and they are widely used in predicting the prognoses of various malignancies. The findings in previous studies are meaningful but still unsatisfactory . Therefore, a new prognostic predictor is required to efficiently assess the patient prognosis. Our study provides three novel FBG-based indexes, which firstly, connected FBG with albumin, lymphocytes, and hemoglobin, in effectively predicting the prognosis of pNEN patients, and also identified their metastases prior to treatment. As far as we know, these three indicators have not been previously reported.
|
[
"Li Yu",
"Mengfei Fu",
"Liu Yang",
"Hui Sun"
] |
https://doi.org/10.3390/jpm14070760
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999994 |
PMC11277919_p19
|
PMC11277919
|
sec[3]/p[1]
|
4. Discussion
| 4.105469 |
biomedical
|
Study
|
[
0.99951171875,
0.00038743019104003906,
0.00021648406982421875
] |
[
0.9990234375,
0.00019097328186035156,
0.0005865097045898438,
0.00007790327072143555
] |
Although earlier studies suggested other reliable indexes, such as APAR and neutrophil-to-lymphocyte ratio, there were limitations when they were used as independent factors . For instance, in a previous study, APAR was shown to be associated with recurrence-free survival of pNEN patients in the nonmetastatic cohort, but failed to play the prediction role in the multivariate analysis . Moreover, no statistical correlation was found between APAR and OS . In contrast, our study found that the cutoff values of FAR, FLR, and FHR not only significantly distinguished the PFS and OS of the total pNEN patients, the univariate and multivariate analyses also revealed that the FAR was an independent predictor of OS for these patients. The FAR was also an independent factor for detecting patients with pNEN and metastasis according to the multivariate analysis. Additionally, a lower FAR was associated with better PFS and OS in these patients. Therefore, our study demonstrated the effectiveness of pretreatment FAR in detecting metastasis prior to therapy and predicting their prognosis after treatment. Moreover, the FLR was an independent predictor of PFS for the total patients. Although the FHR is effective for predicting PFS and OS in pNEN patients, it was not an independent indicator according to the multivariate analysis. Taken together, our results suggested that the FBG-based indices could be the promising indicators for prognosis and identifying the synchronous metastases, especially combining the FAR with FLR.
|
[
"Li Yu",
"Mengfei Fu",
"Liu Yang",
"Hui Sun"
] |
https://doi.org/10.3390/jpm14070760
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999999 |
PMC11277919_p20
|
PMC11277919
|
sec[3]/p[2]
|
4. Discussion
| 4.199219 |
biomedical
|
Study
|
[
0.99951171875,
0.00025200843811035156,
0.00021779537200927734
] |
[
0.99853515625,
0.00019156932830810547,
0.0014200210571289062,
0.00006979703903198242
] |
Previous research reported that the random blood sugar level was connected with a linearly increased risk of all cancers, and type 2 diabetes mellitus (T2DM) also raised the risk of cancer mortality by 26% . In contrast, fasting settings can lead to differential stress sensitization, which makes distinct tumors susceptible to chemotherapy and other therapies while also killing cancer cells as effectively as chemotherapy . Thus, FBG does affect the development of malignancies, and a higher FBG level promotes the progression of cancer. However, the mechanism between FBG and cancer progression remains clarified. The high level of FBG could disturb the homeostatic balance of some endogenous mediators, such as insulin and insulin-like growth factors, which is pro-tumorgenic . Additionally, during the high FBG state, the phosphoinositide-3-kinase (PI-3K), hyperglycemia-associated transcriptional, post-transcriptional factors, and AMP-activated protein kinase probably also contribute to the advancement of cancer . For instance, because the PI-3K singling pathway is crucial for the energy consumption of tumor cells, inhibiting PI-3K could effectively hinder the tumor growth . In hyperglycemia, the integrity of the cellular DNA can be drastically jeopardized, the expression of messenger RNA, long non-coding RNA, and microRNA can be modified, and the post-translational modifications like acetylation can also be altered . In the present study, the groups of higher FAR, FLR, and FHR all presented worse outcomes as compared with lower cohorts, which echoed with the findings mentioned above.
|
[
"Li Yu",
"Mengfei Fu",
"Liu Yang",
"Hui Sun"
] |
https://doi.org/10.3390/jpm14070760
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11277919_p21
|
PMC11277919
|
sec[3]/p[3]
|
4. Discussion
| 4.121094 |
biomedical
|
Study
|
[
0.99951171875,
0.0002982616424560547,
0.00023317337036132812
] |
[
0.9990234375,
0.0002193450927734375,
0.0008068084716796875,
0.0000623464584350586
] |
The nutrition status of a patient plays an important role in cancer development. A prior study demonstrated that the low albumin correlated with a higher risk of negative outcomes . As we all know, cancer cells have a high demand for amino acids to support their proliferation, like serine and glutamine. Serine is necessary for cancer cells to synthesize nucleotide, and glutamine provides the main source of nitrogen to sustain the biosynthesis of new molecules . The decomposition products of albumin could provide these amino acids. The progressive cancer cells with chronic wasting biology could consume an amount of albumin, and a lower level of albumin implies a more advanced stage of disease, which was linked to a worse prognosis . In addition to the impact on the metabolism, hypoalbuminemia also affects the immunity, such as inducing the cytokines of tumor necrosis factor-a, interleukin-6, and interleukin-1, which promotes the cancer progression . Taken together, hyperglycemia or low albumin means a higher FAR, which is theoretically correlated with poor outcomes. This notion was supported by the findings of our study, which indicated that the low-FAR group had considerably longer PFS and OS.
|
[
"Li Yu",
"Mengfei Fu",
"Liu Yang",
"Hui Sun"
] |
https://doi.org/10.3390/jpm14070760
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999994 |
PMC11277919_p22
|
PMC11277919
|
sec[3]/p[4]
|
4. Discussion
| 4.097656 |
biomedical
|
Study
|
[
0.99951171875,
0.00024008750915527344,
0.00019669532775878906
] |
[
0.9990234375,
0.000186920166015625,
0.0006031990051269531,
0.000060439109802246094
] |
Hemoglobin also implies the nutritional status to some extent, and recent studies found that hemoglobin is associated with cancer immunity, which attracts growing attention . On the one hand, malignancies during progression suppress the synthesis of hemoglobin, and anemia is very common in patients with cancer . However, the relationship between hemoglobin and the cancer patients’ outcome has been rarely investigated. The decrease in hemoglobin concentration induces the hypoxic condition, which promotes the invasive phenotype of cancer cells, stimulates neovascularization in tumor tissue via vascular endothelial growth factor signaling pathway, inhibits tumor immune microenvironment, and accelerates cancer progression . The lower hemoglobin concentration has been reported to be associated with a poor prognosis in certain cancers . However, the single parameter of hemoglobin may not be stable enough for prediction . Thereby, a higher hemoglobin concentration, consistent with a lower FBG level, theoretically suggests better outcomes. Our study also demonstrated this hypothesis in which a lower FHR was associated with better outcomes in pNEN patients.
|
[
"Li Yu",
"Mengfei Fu",
"Liu Yang",
"Hui Sun"
] |
https://doi.org/10.3390/jpm14070760
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999995 |
PMC11277919_p23
|
PMC11277919
|
sec[3]/p[5]
|
4. Discussion
| 4.0625 |
biomedical
|
Study
|
[
0.99951171875,
0.0002601146697998047,
0.0001735687255859375
] |
[
0.9990234375,
0.0001837015151977539,
0.0006303787231445312,
0.00007051229476928711
] |
Lymphocytes play a central role in human immunity, which is vital for immunological surveillance and specific anti-tumor immune responses. Higher numbers of lymphocytes may have more reservations and stronger antitumor effects. Research in recent decades has demonstrated that tumor-infiltrating lymphocytes, recruited from circulating blood, are critical for tumor growth. Katz et al. recently demonstrated that a reduced level of tumor-infiltrating lymphocytes is significantly associated with worse PFS in patients with neuroendocrine tumors after resection . Previous study demonstrated that the lymphocyte-based indexes, such as the neutrophil-to-lymphocyte ratio and lymphocyte-to-monocyte ratio, could be effective predictors for various malignancies after treatment . The result of the present study demonstrated that the novel indicator of FHR was significantly correlated with the prognosis of pNEN patients after resection, that is, a lower FHR with better PFS and OS.
|
[
"Li Yu",
"Mengfei Fu",
"Liu Yang",
"Hui Sun"
] |
https://doi.org/10.3390/jpm14070760
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11277919_p24
|
PMC11277919
|
sec[3]/p[6]
|
4. Discussion
| 3.136719 |
biomedical
|
Study
|
[
0.99853515625,
0.0007386207580566406,
0.00086212158203125
] |
[
0.97802734375,
0.01953125,
0.001880645751953125,
0.000576019287109375
] |
Interestingly, our results demonstrated the value of FAR for distinguishing synchronous metastasis in pNEN patients. Metastasis seriously affects the prognosis of pNEN patients , and early detection of metastasis could provide important messages for doctors’ decision-making in the following practices, which would help improve the treatment outcomes of these patients. However, the mechanism between a lower FAR and better prognosis requires further investigation.
|
[
"Li Yu",
"Mengfei Fu",
"Liu Yang",
"Hui Sun"
] |
https://doi.org/10.3390/jpm14070760
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277919_p25
|
PMC11277919
|
sec[3]/p[7]
|
4. Discussion
| 1.989258 |
biomedical
|
Study
|
[
0.99609375,
0.0014286041259765625,
0.0025615692138671875
] |
[
0.9521484375,
0.04473876953125,
0.00193023681640625,
0.0010213851928710938
] |
There is a limitation in the study to be mentioned. This is a single-center retrospective study and selection bias could not be avoided, although the patient number included in this study is large in the pNEN cohort and is followed up in a long-term period.
|
[
"Li Yu",
"Mengfei Fu",
"Liu Yang",
"Hui Sun"
] |
https://doi.org/10.3390/jpm14070760
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11277919_p26
|
PMC11277919
|
sec[4]/p[0]
|
5. Conclusions
| 4.023438 |
biomedical
|
Study
|
[
0.99951171875,
0.000377655029296875,
0.00015842914581298828
] |
[
0.9990234375,
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0.0006489753723144531,
0.00009942054748535156
] |
Our study provides three novel FBG-based indices, including FAR, FLR, and FHR, which are effective in predicting the prognosis of pNEN patients, as well as detecting their metastases prior to treatment. These markers are inexpensive and easily available in clinical practice, which supports surgeons in making optimal therapy and surveillance strategies for individuals. Moreover, these novel markers have the potential of predicting the outcomes of various other malignancies.
|
[
"Li Yu",
"Mengfei Fu",
"Liu Yang",
"Hui Sun"
] |
https://doi.org/10.3390/jpm14070760
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
39057381_p0
|
39057381
|
sec[0]/p[0]
|
1. Introduction
| 4.632813 |
biomedical
|
Study
|
[
0.9990234375,
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] |
[
0.9794921875,
0.0011806488037109375,
0.0192413330078125,
0.0002598762512207031
] |
Unsaturated fatty acids (UFAs), which are structural components of cell membrane phospholipids and signal transduction molecules, play a vital physiological role in the stress response of living organisms. Microorganisms acclimate to environmental factors such as nutrient supply, temperature, pH, humidity, pressure, and ionic strength by maintaining a proper proportion of liquid crystal lipids and cell membrane balance to prevent membrane injury and destruction. The mechanism includes altering the fatty acid composition of membrane phospholipids by changing the degree of fatty acid unsaturation and decreasing the lengths of fatty acid chains . Heat stress increases the fluidity of the cytoplasmic membrane . The degree of unsaturation of fatty acids in cell membrane lipids is widely accepted as a determinant of membrane fluidity and has previously been reported in animals, plants, bacteria, and fungi . Fatty acid desaturases, key enzymes in UFA biosynthesis, are nearly ubiquitous in living organisms and are the core regulators of many physiological reactions. Their function is to insert double bonds into the alkyl chain after removing two hydrogen atoms . The first step in the synthesis of UFAs is the formation of linoleic acid. FAD2 converts oleate (18:1) to linoleate (18:2), and the expression of the FAD2 protein is temperature dependent. Research on FAD2 is particularly important for the regulation of the heat stress response in living organisms .
|
[
"Huanling Yang",
"Jun Jiang",
"Mingjie Chen",
"Xiaoxia Song",
"Changxia Yu",
"Hongyu Chen",
"Yan Zhao"
] |
https://doi.org/10.3390/jof10070496
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999995 |
39057381_p1
|
39057381
|
sec[0]/p[1]
|
1. Introduction
| 4.378906 |
biomedical
|
Study
|
[
0.9990234375,
0.0004146099090576172,
0.0004916191101074219
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[
0.99951171875,
0.00021898746490478516,
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0.00008475780487060547
] |
The basidiomycete Lentinula edodes (Berkeley) Pegler, known as a famous edible mushroom (shiitake), is the most economically important cultivated mushroom in East Asia and the second most popular mushroom throughout the world . L. edodes is a type of mushroom that fruits at low temperature, and fruiting bodies of the shiitake mushroom are produced at 8–20 °C. However, the temperature of the main mushroom-producing areas in China during summer is much higher than 25 °C, causing the mycelia to become yellow or even stop growing. The agronomic characteristics of the fruiting bodies become poor (small fruiting bodies, thin cap, and less open umbrellas), seriously affecting fresh mushroom production during summer. The fluidity of the membrane is positively correlated with the unsaturation of fatty acids. Under the stimulation of rising temperature, the expression of the FAD gene, which transforms saturated fatty acids (SFAs) into UFAs, decreases to increase lipid saturation, thereby reducing membrane fluidity and maintaining it in the optimal state for normal biological function . The tolerance of organisms to high temperature is proportional to the content of SFAs and inversely proportional to the content of UFAs. In bacteria, when Lactobacillus coryniformis Si3 was fermented at 42 °C for 6 h, the degree of membrane fatty acid saturation was significantly reduced, indicating that the thermal tolerance of lactic acid bacteria is closely linked with the synthesis of membrane fatty acids . In fungi, fatty acids are related to temperature-induced stress and the formation of fruiting bodies in L. edodes . In preliminary work, we evaluated the nutritional value of L. edodes mycelia and determined the compositions and contents of fatty acids and amino acids . In this study, the fatty acid content changes in the mycelia of L. edodes strains 18 and 18N44 were determined by GC-MS after growth at 37 °C for different durations (0, 4, 8, 12, 18, and 24 h). The results showed that a negative correlation exists between the proportion of UFAs in L. edodes and its heat tolerance under high temperature, which provides a theoretical basis for the breeding of new varieties of L. edodes with better high-temperature tolerance . In addition, the role of FAD2 in the synthesis of linoleic acid was analyzed. We investigated the bioinformatic characteristics, elucidated the phylogenetic relationships between the homologous sequences of the FAD2 gene and the corresponding proteins in L. edodes , and examined the effects of FAD2 gene expression on linoleic acid production under different heat stresses.
|
[
"Huanling Yang",
"Jun Jiang",
"Mingjie Chen",
"Xiaoxia Song",
"Changxia Yu",
"Hongyu Chen",
"Yan Zhao"
] |
https://doi.org/10.3390/jof10070496
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
39057381_p2
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2.1. Strains
| 3.564453 |
biomedical
|
Study
|
[
0.994140625,
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] |
[
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0.00011491775512695312
] |
L. edodes strain 18 is an off-season cultivated variety, and strain 18N44 is obtained from strain 18 by UV mutagenesis . Our research group identified two strains (strain 18 and strain 18N44) by ISSR and identified 18N44 as a new strain. In addition, 18N44 has the characteristics of rapid recovery and early emergence of fruiting bodies after being subjected to high-temperature stress during cultivation. In our previous studies, we determined the temperature and duration of high-temperature stress treatment . L. edodes strain 18 and the mutagenic heat-tolerant strain 18N44 were obtained from the Institute of Edible Fungi, Shanghai Academy of Agricultural Sciences.
|
[
"Huanling Yang",
"Jun Jiang",
"Mingjie Chen",
"Xiaoxia Song",
"Changxia Yu",
"Hongyu Chen",
"Yan Zhao"
] |
https://doi.org/10.3390/jof10070496
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
39057381_p3
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39057381
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2.2. Acquisition of Gene Sequences
| 3.958984 |
biomedical
|
Study
|
[
0.99951171875,
0.00015413761138916016,
0.0003478527069091797
] |
[
0.99853515625,
0.0009822845458984375,
0.00019085407257080078,
0.00006914138793945312
] |
Six homologous genes of FAD2 were found and downloaded from the NCBI genome database of L. edodes strain W1-26 or the genome database of L. edodes and were named FAD2-2 , FAD2-3 , FAD2-4 , FAD2-5 , FAD2-6 , and FAD2-8 . The six homologous genes were translated into amino acid sequences by BLAST for bioinformatic analysis.
|
[
"Huanling Yang",
"Jun Jiang",
"Mingjie Chen",
"Xiaoxia Song",
"Changxia Yu",
"Hongyu Chen",
"Yan Zhao"
] |
https://doi.org/10.3390/jof10070496
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
39057381_p4
|
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sec[1]/sec[2]/p[0]
|
2.3. Bioinformatic Analysis
| 4.140625 |
biomedical
|
Study
|
[
0.99951171875,
0.00023865699768066406,
0.00017917156219482422
] |
[
0.9990234375,
0.0003094673156738281,
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0.00007206201553344727
] |
The protein sequences of homologous FAD2 genes were analyzed by the following online tools. Multiple sequence alignment of the FAD2 loci was performed with T-Coffee under the default settings. Protein properties were then predicted by bioinformatics tools based on analysis of the FAD2 sequences. Amino acid and atom compositions, molecular weights, and theoretical pI values were estimated by ExPASy ProtParam . SignalP 4.1 , TMHMM 2.0 , and TargetP 2.0 were used to predict signal peptides, transmembrane helices, and subcellular localization, respectively .
|
[
"Huanling Yang",
"Jun Jiang",
"Mingjie Chen",
"Xiaoxia Song",
"Changxia Yu",
"Hongyu Chen",
"Yan Zhao"
] |
https://doi.org/10.3390/jof10070496
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
39057381_p5
|
39057381
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2.4. Heat Stress Treatment
| 4.105469 |
biomedical
|
Study
|
[
0.99951171875,
0.0003333091735839844,
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] |
[
0.99951171875,
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0.00025153160095214844,
0.00005626678466796875
] |
Researchers have shown that the effects of abiotic stress on the mycelia of L. edodes are minimal at a temperature of 25 °C . For heat stress, mycelia of strains 18 and 18N44 were inoculated on the surface of solid potato dextrose agar (PDA) plates with a diameter of 9 cm and cultured in the dark for two weeks at 25 °C. Plates covered with mycelia were placed in a blender with culture solution, and 10 mL of the resulting solution was transferred to a shaking flask (250 mL flasks containing 100 mL of potato dextrose broth (PDB) medium (Becton, Dickinson and Company Sparks, Franklin Lakes, NJ, USA), which was then incubated in a shaker at 150 rpm and 25 °C in darkness for two weeks. When the amount of mycelia in the shaking flask was sufficient, the heat stress test was applied. L . edodes mycelia incubated in liquid PDB medium were subjected to heat stress by growth at 37 °C for 4, 8, 12, 18, or 24 h; mycelia continuously maintained at 25 °C served as controls. Biological duplicates of the heat stress test were performed three times. Following heat stress treatment, mycelia in the incubation buffer were quickly collected and rinsed with sterile water under sterile conditions, flash-frozen in liquid nitrogen and stored at −80 °C for RNA extraction. All treatments were repeated in at least three independent replicates.
|
[
"Huanling Yang",
"Jun Jiang",
"Mingjie Chen",
"Xiaoxia Song",
"Changxia Yu",
"Hongyu Chen",
"Yan Zhao"
] |
https://doi.org/10.3390/jof10070496
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
39057381_p6
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2.5. RNA Extraction and cDNA Reverse Transcription
| 4.085938 |
biomedical
|
Study
|
[
0.99951171875,
0.00019872188568115234,
0.0002148151397705078
] |
[
0.9990234375,
0.0006990432739257812,
0.00026154518127441406,
0.00006324052810668945
] |
The total RNA of the treated L . edodes mycelia was extracted using a Redzol reagent kit (Tiangen Biotech Co., Ltd., Beijing, China) according to the manufacturer’s instructions. RNA integrity was validated by agarose gel (1.5%, w / v ) electrophoresis. A NanoDrop 2000 Spectrophotometer (Thermo Scientific, Rockford, IL, USA) was used to evaluate the quantity and quality of the RNA. RNA extracts with A260/280 absorption ratios in the range of 1.8–2.2 and A260/230 absorption ratios over 1.8 were selected and subsequently subjected to cDNA synthesis.
|
[
"Huanling Yang",
"Jun Jiang",
"Mingjie Chen",
"Xiaoxia Song",
"Changxia Yu",
"Hongyu Chen",
"Yan Zhao"
] |
https://doi.org/10.3390/jof10070496
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999999 |
39057381_p7
|
39057381
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2.6. RT-qPCR Analysis of Gene Expression
| 4.128906 |
biomedical
|
Study
|
[
0.99951171875,
0.00022733211517333984,
0.00022292137145996094
] |
[
0.99951171875,
0.0004324913024902344,
0.00023126602172851562,
0.00006091594696044922
] |
RT-qPCR was performed in a StepOnePlus Real-Time PCR instrument (Applied Biosystems, Foster City, CA, USA) using a SYBR ® Premix Ex Taq™ II (Takara Biomedical Technology, Dalian, China) kit. The reaction system included 10 μL of SYBR ® Premix Ex Taq™ II (2×), 2 μL of template cDNA, 0.4 μL of ROX dye, 0.4 μL of each primer, and 6.8 μL of RNase-free water. The following procedures were used for PCR amplification: denaturation at 95 °C for 30 s, 40 cycles of PCR at 95 °C for 5 s, 60 °C for 15 s, and 72 °C for 15 s, and a melting curve at 95 °C for 15 min, 60 °C for 30 s, and 95 °C for 15 min. According to the 2 −∆∆Ct method, the relative expression of genes was measured . The expression stability of the candidate genes of L. edodes mycelia under heat stress was evaluated using three native statistical software programs: geNorm, NormFinder, and BestKeeper. Our laboratory screened 10 candidate reference genes and found that beta-tubulin ( TUB ) was the most suitable internal reference gene for L. edodes mycelia under heat stress . The qPCR primers that were used were designed with Primer-BLAST and synthesized by Sangon Biotech Co., Ltd. (Shanghai, China). The sequences of the primers used are shown in Table 1 .
|
[
"Huanling Yang",
"Jun Jiang",
"Mingjie Chen",
"Xiaoxia Song",
"Changxia Yu",
"Hongyu Chen",
"Yan Zhao"
] |
https://doi.org/10.3390/jof10070496
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
39057381_p8
|
39057381
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sec[1]/sec[6]/p[0]
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2.7. Detection of Fatty Acid Desaturase (FAD2) by an ELISA Kit
| 4.136719 |
biomedical
|
Study
|
[
0.99951171875,
0.0003046989440917969,
0.00017261505126953125
] |
[
0.99853515625,
0.0007624626159667969,
0.0003924369812011719,
0.00008535385131835938
] |
The fatty acid desaturase (FAD2) enzyme activity was measured on ice using an ELISA kit (Jiangsu Jingmei Biotechnology Co., Ltd., Yancheng, China) according to the manufacturer’s instructions. The mycelia grown on agar media were collected, and 1 g of mycelia was weighed, rinsed with PBS (pH of 7.4), and then rapidly frozen with liquid nitrogen. The sample was homogenized in PBS with a homogenizer on ice. The homogenates were then centrifuged for 20 min at 2000 rpm before the supernatant was removed. The standards or samples were added to the appropriate wells. Then, the enzyme conjugate was added to the well, which was covered with an adhesive strip and incubated at 37 °C for 60 min. The plate was then washed four times with wash buffer. After the final wash, the plates were inverted and blotted dry onto paper towels until no moisture appeared. For coloring, chromogen solutions A and B were added to each well, gently mixed, and incubated in the dark at 37 °C for 15 min. Stop solution was then added to each well. The color in the well was observed by reading the optical density at 450 nm using a microtiter plate reader. Four replicates were performed for each test.
|
[
"Huanling Yang",
"Jun Jiang",
"Mingjie Chen",
"Xiaoxia Song",
"Changxia Yu",
"Hongyu Chen",
"Yan Zhao"
] |
https://doi.org/10.3390/jof10070496
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
39057381_p9
|
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|
2.8. Analysis of the Fatty Acid Content by Gas Chromatography-Mass Spectrometry
| 4.101563 |
biomedical
|
Study
|
[
0.99951171875,
0.00021946430206298828,
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] |
[
0.99951171875,
0.0002472400665283203,
0.00022602081298828125,
0.00004792213439941406
] |
The linoleic acid contents in strain 18 and the mutagenic heat-tolerant strain 18N44 under heat stress were analyzed by GC-MS. The heat stress treatments of strains 18 and 18N44 were performed as described in Section 2.4 . After heat stress, the samples were prepared according to the methods described by Yu et al. . Briefly, mycelia (0.2 g) were acidified with 1.0 mL of 5% H 2 SO 4 , and 5 μL of nonadecanoic acid methyl ester (as an internal standard) in a screw-cap tube. The samples were then heated at 80 °C for 90 min every 10 s to eliminate N 2 outgassing, followed by refrigeration at 4 °C for 10 min. After transferring the samples to glass vials, 0.5 mL of water and 1.0 mL of n-hexane were added, and the samples were oscillated for 20 s and then centrifuged at 2000 rpm for 10 min. Next, the supernatants were subjected to GC-MS analysis (Auto-System XL GC and TurboMass MS; Perkin Elmer, Waltham, MA, USA).
|
[
"Huanling Yang",
"Jun Jiang",
"Mingjie Chen",
"Xiaoxia Song",
"Changxia Yu",
"Hongyu Chen",
"Yan Zhao"
] |
https://doi.org/10.3390/jof10070496
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
39057381_p10
|
39057381
|
sec[1]/sec[7]/p[1]
|
2.8. Analysis of the Fatty Acid Content by Gas Chromatography-Mass Spectrometry
| 4.082031 |
biomedical
|
Study
|
[
0.99951171875,
0.00015997886657714844,
0.0003268718719482422
] |
[
0.99853515625,
0.0011320114135742188,
0.00024700164794921875,
0.000058650970458984375
] |
A 60 m HP-5MS capillary column with an inner diameter (i.d.) of 0.25 mm was used (Agilent Technologies, Santa Clara, CA, USA). The GC-MS instrument was programmed to begin at 70 °C for 5 min, followed by a 10 min temperature ramp up to 270 °C at a flow rate of 1 mL/min. Three replicates were performed for each sample. The samples were quantified against the internal standard, and their linoleic acid contents were expressed as the percentage of total fatty acids (FAs) present in each sample.
|
[
"Huanling Yang",
"Jun Jiang",
"Mingjie Chen",
"Xiaoxia Song",
"Changxia Yu",
"Hongyu Chen",
"Yan Zhao"
] |
https://doi.org/10.3390/jof10070496
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
39057381_p11
|
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2.9. Statistical Analysis
| 2.357422 |
biomedical
|
Study
|
[
0.99755859375,
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0.0018358230590820312
] |
[
0.79052734375,
0.2049560546875,
0.003398895263671875,
0.0012216567993164062
] |
The data were obtained from three independent replicates. Unless indicated otherwise, the data are presented as the mean ± standard error of the mean. Student’s t test was used for the statistical analyses. The histogram was drawn with GraphPad Prism 6 (GraphPad Software, Inc., La Jolla, CA, USA).
|
[
"Huanling Yang",
"Jun Jiang",
"Mingjie Chen",
"Xiaoxia Song",
"Changxia Yu",
"Hongyu Chen",
"Yan Zhao"
] |
https://doi.org/10.3390/jof10070496
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
39057381_p12
|
39057381
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3.1. Sequence Alignment and Phylogenetic Profile of the FAD2 Protein
| 4.167969 |
biomedical
|
Study
|
[
0.99951171875,
0.0003333091735839844,
0.0003674030303955078
] |
[
0.99951171875,
0.00016117095947265625,
0.0002453327178955078,
0.0000603795051574707
] |
To elucidate the phylogenetic relationships of the FAD2 genes, six protein sequences were aligned. The genes were divided into two large clusters in a maximum likelihood phylogenetic tree . Among these sequences, the FAD2-3 , FAD2-4 , FAD2-5 , and FAD2-6 sequences from L. edodes mycelia grouped into one large cluster, and FAD2-6 and FAD2-4 belonged to the same clade with a bootstrap value of 100%. The FAD2-2 and FAD2-8 sequences were grouped into the second cluster. Figure 1 B shows the relative positional distribution of the FAD2 intron in L. edodes mycelia. The positions of the FAD2-5 introns are quite different from those of the other FAD2 genes. FAD2-2 , FAD2-4 , and FAD2-6 each had 8 introns. Meanwhile, FAD2-3 contained 6 introns, which was the lowest among all the FAD2 genes. The distribution of introns was basically consistent with the results of phylogenetic tree classification.
|
[
"Huanling Yang",
"Jun Jiang",
"Mingjie Chen",
"Xiaoxia Song",
"Changxia Yu",
"Hongyu Chen",
"Yan Zhao"
] |
https://doi.org/10.3390/jof10070496
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
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3.1. Sequence Alignment and Phylogenetic Profile of the FAD2 Protein
| 4.285156 |
biomedical
|
Study
|
[
0.99951171875,
0.0003452301025390625,
0.00032806396484375
] |
[
0.99951171875,
0.0001914501190185547,
0.0003230571746826172,
0.00007641315460205078
] |
The close alignment of six homologous protein sequences from L. edodes was examined using the T-Coffee program . T-Coffee is a multiple sequence alignment program, and its main feature is combining results obtained using several alignment methods. The results showed that these protein sequences were strongly conserved . The alignment revealed that all the FAD2 polypeptide sequences contained strongly conserved histidine motifs . The first histidine motif was HXXXH, and the second histidine motif was HXXHH. The second motif is highly conserved in the FAD2 sequence and repeats toward the carboxyl terminus of each sequence. The third motif consisted of three histidine residues. These three histidine motifs are the main functional regions involved in FAD2 activity. Sakai et al. deduced that the Le-FAD2 protein has three typical histidine clusters (HXXXH, HXXHH, and HXXHH), and the catalytic domain of the Le-FAD2 enzyme is conserved in L. edodes , which was consistent with our analysis. The distance between the first and second motifs was relatively short (approximately 31 residues), while the distance between the second and third motifs was relatively long (approximately 202 residues), which is similar to findings in other species.
|
[
"Huanling Yang",
"Jun Jiang",
"Mingjie Chen",
"Xiaoxia Song",
"Changxia Yu",
"Hongyu Chen",
"Yan Zhao"
] |
https://doi.org/10.3390/jof10070496
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
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3.2. Bioinformatic Analysis of Homologous FAD2 Proteins in L. edodes
| 4.144531 |
biomedical
|
Study
|
[
0.99951171875,
0.00022995471954345703,
0.0003445148468017578
] |
[
0.99951171875,
0.00023734569549560547,
0.0002491474151611328,
0.00005233287811279297
] |
The ExPASy ProtParam online analysis tool was used to predict the basic physical and chemical properties of homologous FAD2 proteins from L. edodes . The number of amino acid residues, molecular formula, and isoelectric point of each protein are shown in Table 2 . Based on the amino acid composition and the instability index, FAD2-2, FAD2-3, FAD2-5, and FAD2-8 were classified as stable proteins, while FAD2-4 and FAD2-6 were classified as unstable proteins. The proteins encoded by FAD2-2 and FAD2-6 are hydrophobic. FAD2-2 and FAD2-8 are acidic proteins, which is consistent with their predicted isoelectric points.
|
[
"Huanling Yang",
"Jun Jiang",
"Mingjie Chen",
"Xiaoxia Song",
"Changxia Yu",
"Hongyu Chen",
"Yan Zhao"
] |
https://doi.org/10.3390/jof10070496
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999999 |
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3.2. Bioinformatic Analysis of Homologous FAD2 Proteins in L. edodes
| 4.160156 |
biomedical
|
Study
|
[
0.99951171875,
0.0002579689025878906,
0.0002779960632324219
] |
[
0.99951171875,
0.0001609325408935547,
0.00025653839111328125,
0.00006157159805297852
] |
The two algorithms, TargetP and SignalP 4.1 , were used to predict protein sorting signals in the N-terminal region of the FAD2 sequences and the cellular localization sites of these proteins. Based on these results, FAD2-3 was the only protein located in the mitochondrial pathway, and FAD2-6 was the only protein located in the secretory pathway ( Table S1 ). Transmembrane helices were predicted in homologous FAD2 proteins from L. edodes using TMHMM 2.0 . The numbers of transmembrane domains among homologous FAD2 proteins are different, and the results are shown in Figure 3 . FAD2-4 and FAD2-6 were confirmed to have five transmembrane domains, while six transmembrane helices were predicted in FAD2-2 and FAD2-8. No transmembrane helices were present in FAD2-3 or FAD2-5.
|
[
"Huanling Yang",
"Jun Jiang",
"Mingjie Chen",
"Xiaoxia Song",
"Changxia Yu",
"Hongyu Chen",
"Yan Zhao"
] |
https://doi.org/10.3390/jof10070496
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
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3.3. Differential Expression of FAD2 Genes under Heat Stress
| 4.210938 |
biomedical
|
Study
|
[
0.9990234375,
0.0003371238708496094,
0.00040268898010253906
] |
[
0.99951171875,
0.00014793872833251953,
0.00023412704467773438,
0.000055909156799316406
] |
The transcriptional responses of six homologous FAD2 genes to heat stress were tested by incubating the mycelia of L. edodes under heat stress at 37 °C for 4, 8, 12, 18, and 24 h; mycelia that had been incubated at 25 °C were used as the control group. After the 18 and 18N44 strains were exposed to heat stress for different durations, RNA was extracted, and reverse transcription and RT-qPCR were subsequently performed to analyze the transcript levels of the FAD2 genes. The heat-treated mycelia of strain 18 generally had lower levels of these transcripts than the unheated control samples . However, the heat-treated mycelia of strain 18N44 showed different trends in the expression levels of the six homologous FAD2 genes compared with those of the unheated control samples. After heat stress, FAD2-2 , FAD2-5 (except for 18 h), and FAD2-6 genes had lower transcript levels than those in the unheated control samples, and the transcript levels of all of these genes first decreased and then increased. The transcript level of FAD2-3 decreased slightly compared with that of the unheated control sample during heat stress, whereas the expression level was significantly greater than that of the control at 24 h ( p < 0.05). In addition, the transcript level of the FAD2-8 gene was greater than that in the unheated control sample, which continued to increase with prolonged heat stress. Meanwhile, the transcript level of FAD2-4 fluctuated greatly during heat stress and could be greater or less than that in the unheated control sample. The FAD2-4, FAD2-5 (except for 24 h), FAD2-6 (except for 4 h and 18 h), and FAD2-8 transcript levels were greater in strain 18N44 than in strain 18, but the FAD2-2 (except for 0 h and 12 h, and no significant difference at 24 h) and FAD2-3 (except for 24 h) transcript levels were lower in strain 18N44.
|
[
"Huanling Yang",
"Jun Jiang",
"Mingjie Chen",
"Xiaoxia Song",
"Changxia Yu",
"Hongyu Chen",
"Yan Zhao"
] |
https://doi.org/10.3390/jof10070496
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
39057381_p17
|
39057381
|
sec[2]/sec[3]/p[0]
|
3.4. Activity of FAD2 under Heat Stress
| 3.240234 |
biomedical
|
Study
|
[
0.99609375,
0.0003342628479003906,
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[
0.99267578125,
0.0066375732421875,
0.0002911090850830078,
0.00015366077423095703
] |
The enzyme activity of FAD2 in strain 18N44 was lower than that in strain 18. With prolonged heat stress, the activity of FAD2 in strain 18 significantly decreased, while that in strain 18N44 did not significantly change, which may be one of the reasons why strain 18N44 was more resistant to heat stress than strain 18 .
|
[
"Huanling Yang",
"Jun Jiang",
"Mingjie Chen",
"Xiaoxia Song",
"Changxia Yu",
"Hongyu Chen",
"Yan Zhao"
] |
https://doi.org/10.3390/jof10070496
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
39057381_p18
|
39057381
|
sec[2]/sec[4]/p[0]
|
3.5. Analysis of the Linoleic Acid Contents of 18 and 18N44 under Heat Stress
| 4.121094 |
biomedical
|
Study
|
[
0.99951171875,
0.00021016597747802734,
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[
0.99951171875,
0.0002684593200683594,
0.00016307830810546875,
0.00004214048385620117
] |
Linoleic acid was the main UFA in L. edodes strain 18 and the mutagenic heat-tolerant strain 18N44 . Gas chromatography-mass spectrometry (GC-MS) was used to determine the linoleic acid content in both strains under heat stress (0, 4, 8, 12, 18, and 24 h). The linoleic acid content decreased significantly after 24 h of heat stress and was significantly greater in strain 18 than in strain 18N44 during heat stress .
|
[
"Huanling Yang",
"Jun Jiang",
"Mingjie Chen",
"Xiaoxia Song",
"Changxia Yu",
"Hongyu Chen",
"Yan Zhao"
] |
https://doi.org/10.3390/jof10070496
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
39057381_p19
|
39057381
|
sec[3]/p[0]
|
4. Discussion
| 4.480469 |
biomedical
|
Study
|
[
0.9990234375,
0.00046896934509277344,
0.0003459453582763672
] |
[
0.9990234375,
0.0003008842468261719,
0.0006103515625,
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] |
FAD2s are widely found in various living organisms, including higher plants, green algae, fungi, animals, and other eukaryotes, as well as prokaryotes such as bacteria. Six FAD2 family candidate genes were obtained by comparing the protein sequences of L. edodes in this study. According to the phylogenetic tree construction and protein physicochemical property analysis, the six FAD2 family members were divided into two large clusters. The distribution of introns was generally consistent with the results of phylogenetic tree classification. Great differences exist in the physicochemical properties of the FAD2 protein family members, including differences in amino acid number, isoelectric points, molecular weight, stability, hydrophilicity, and transmembrane domain. However, they all have highly conserved amino acid regions, mainly histidine-enriched segments. Transmembrane domains, histidine motifs, and ER retrieval motifs are commonly found in FAD2 proteins and are considered typical features of FADs . Multiple alignment of six homologous protein sequences from L. edodes indicated that they had three regions with strongly conserved histidine motifs (HXXXH, HXXHH, and HXXHH), which had a total of eight histidine residues. These histidine residues are essential for enzymatic catalytic activities and are inferred to act as ligands for the iron atoms in homolog stearoyl CoA desaturase in oilseeds . Mutations at any site of the motif result in the failure of enzyme–endoplasmic reticulum (ER) coupling and attachment to the plasma membrane. The three histidine motifs, located in the N-terminal region (active center of the enzyme), are critical for enzymatic functioning. Their localization requires hydrophobic residues, and amino acid substitution results in the loss of desaturase activity . However, for the homologous FAD2 proteins from L. edodes , FAD2-3 and FAD2-5 have no transmembrane helices. These results may indicate consistency among members of the same subfamily and great variation among different subfamilies during the evolution of the L. edodes FAD2 family. Many studies have described the important role of the FAD2 gene in plants . However, the function of FAD2 proteins during fungal responses to abiotic stress has rarely been reported.
|
[
"Huanling Yang",
"Jun Jiang",
"Mingjie Chen",
"Xiaoxia Song",
"Changxia Yu",
"Hongyu Chen",
"Yan Zhao"
] |
https://doi.org/10.3390/jof10070496
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
39057381_p20
|
39057381
|
sec[3]/p[1]
|
4. Discussion
| 4.28125 |
biomedical
|
Study
|
[
0.9990234375,
0.0003459453582763672,
0.0004520416259765625
] |
[
0.99951171875,
0.0001780986785888672,
0.0003218650817871094,
0.00006496906280517578
] |
The FAD gene encodes a key enzyme involved in the production of polyunsaturated fatty acids, which play an important role in plant cold resistance , but studies on the regulation of the expression of this gene under high-temperature stress have rarely been reported. Zhang et al. reported that the expression of FAD3 and FAD8 reduced the resistance of tobacco to high-temperature stress . Silencing of the FAD7 gene in tobacco plants can increase the ability of the plants to acclimate to relatively high temperatures . Li et al. reported that CtFAD2-1 , CtFAD2-2 , and CtFAD6 were significantly induced in young leaves under cold and heat stress and CtFAD2-2 and CtFAD6 were slightly induced in young stems of safflower . Saccharomyces cerevisiae cells transformed with the FAD2-1 gene of sunflowers exhibited the highest percentage of dienoic acids at 10 °C, and the percentage of dienoic acids decreased at higher temperatures . The expression of Caenorhabditis elegans Δ12 fatty acid desaturase in Saccharomyces cerevisiae cells resulted in the accumulation of 16:2 and 18:2 (linoleic) acids and a growth rate advantage for cells at 12 °C . More studies on Saccharomyces cerevisiae and Rhodotorula toruloides have indicated that the fatty acid desaturase and FAD genes are involved in the stress response to temperature . In addition, Sakai et al. studied Le-FAD1 and Le-FAD2 in L. edodes and reported that the transcription levels of Le-FAD1 mRNA in the primordium and fruiting body of L. edodes were greater than those in mycelia cultivated at 18 °C or 25 °C . In addition, a reduction in growth temperature from 25 °C to 18 °C had no effect on the transcription level of Le-FAD2 . However, further research on the expression of Le-FAD1 and Le-FAD2 under heat stress has not been conducted. In our research, the expression of six homologous FAD2 genes after heat stress at 37 °C was investigated by RT-qPCR. The results showed that all six FAD2 genes participated in the heat stress response in L. edodes . In particular, the transcription levels of the FAD2-2 , FAD2-3 , FAD2-5 , and FAD2-6 genes in strains 18 and 18N44 were lower than those in the control sample during heat stress. The transcription levels of FAD2-2 tended to first decrease and then increase in both strain 18 and strain 18N44, with the lowest values occurring at 12 h and 8 h, respectively, indicating that the FAD2-2 gene in strain 18N44 responded to heat stress earlier than that in strain 18. The transcription levels of FAD2-3 in strains 18 and 18N44 continued to decrease with prolonged heat stress time (except for 12 h in strain 18 and 24 h in strain 18N44), and the degree of decline in strain 18N44 was smaller than that in strain 18, indicating that the FAD2-3 gene in strain 18N44 was less affected by heat stress than that in strain 18. The transcription level of FAD2-5 fluctuated greatly in strain 18, while the transcription level of FAD2-5 first decreased then increased, and finally decreased again in strain 18N44 (the inflection points occurred at 8 h and 18 h, respectively). The transcription level of FAD2-6 in strain 18 first decreased and then increased (the lowest value appeared at 12 h), while it fluctuated significantly in strain 18N44. During heat stress, the transcription levels of FAD2-2 and FAD2-3 in strain 18N44 were generally lower than those in strain 18, while the transcription levels of FAD2-5 in strain 18N44 were greater than those in strain 18. In general, FAD2-2 and FAD2-3 may play major roles in strains 18 and 18N44 under heat stress.
|
[
"Huanling Yang",
"Jun Jiang",
"Mingjie Chen",
"Xiaoxia Song",
"Changxia Yu",
"Hongyu Chen",
"Yan Zhao"
] |
https://doi.org/10.3390/jof10070496
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999993 |
39057381_p21
|
39057381
|
sec[3]/p[2]
|
4. Discussion
| 4.257813 |
biomedical
|
Study
|
[
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0.00046539306640625
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[
0.99951171875,
0.00026679039001464844,
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0.000059664249420166016
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Studies have shown that changes in FAD activity are closely related to the plant response to heat stress, and FAD is involved in regulating the fluidity of the cell membrane and reducing heat stress damage by catalyzing the desaturation of fatty acids; namely, a double bond is introduced into fatty acid chains, thus increasing the proportion of unsaturated fatty acids . FAD2, an enzyme closely related to oleic acid 12-hydroxylase, which hydroxylates oleic acid to ricinoleic acid, catalyzes the formation of linoleic acid (18:2) from oleic acid (18:1) . Our research showed that the enzyme activity of FAD2 decreased in strain 18 after heat stress but did not significantly change in strain 18N44, and the enzyme activity of strain 18N44 was lower than that of strain 18, which was consistent with the changes in the transcription levels of the FAD2-2 and FAD2-3 genes. This may be because the proportion of unsaturated fatty acids was reduced in strain 18 by reducing FAD2 activity after heat stress, thus reducing the damage caused by heat stress. Owing to the greater thermostability of strain 18N44, which did not significantly change after heat stress, strain 18N44 showed lower activity than strain 18, suggesting that high temperature had a greater effect on the heat-sensitive strain 18.
|
[
"Huanling Yang",
"Jun Jiang",
"Mingjie Chen",
"Xiaoxia Song",
"Changxia Yu",
"Hongyu Chen",
"Yan Zhao"
] |
https://doi.org/10.3390/jof10070496
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
39057381_p22
|
39057381
|
sec[3]/p[3]
|
4. Discussion
| 4.347656 |
biomedical
|
Study
|
[
0.99951171875,
0.0003681182861328125,
0.0002601146697998047
] |
[
0.99951171875,
0.0002263784408569336,
0.00039196014404296875,
0.00010734796524047852
] |
Membrane adaptation to temperature shifts highly depends on adjusting the saturation of fatty acids in membrane lipids . At high growth temperatures, the primary change was the downregulation of linoleic acid and the upregulation of SFAs . After heat stress, PUFA (C18:3) levels in wheat flag leaves decrease during grouting, while the amounts of hexadecenoic acid (C16:1) and linoleic acid (C18:2) increase . These results indicate that the lipid composition of wheat cell membranes changes under thermal stress, which may be an adaptive plant response to heat stress. FA composition analysis of Histoplasma capsulatum mycelia suggested that a temperature-tolerant strain (G217B) had a greater SFA concentration and a higher SFA/UFA ratio than did a temperature-sensitive strain . Studies in soybean, Arabidopsis, and other plants have also yielded similar results . In this study, GC-MS was used to analyze the linoleic acid content of heat-stressed mycelia of strain 18 and the mutagenic heat-tolerant strain 18N44. The 18N44 strain is more tolerant to heat stress, and its linoleic acid content is lower than that of heat-sensitive strain 18. Many reports indicate that the UFA content is positively correlated with cold resistance and that FAD2 genes are directly involved in membrane adaptation to temperature stress . This explains the critical role of FAD in regulating membrane fluidity by regulating the degree of fatty acid unsaturation, thereby enhancing resistance to physiological stresses. Our results showed that the transcription levels of the FAD2-2 and FAD2-3 genes and the enzyme activity of FAD2 decreased significantly in strain 18 after heat stress, and a decrease in the linoleic acid content was simultaneously detected, which is similar to the results mentioned above.
|
[
"Huanling Yang",
"Jun Jiang",
"Mingjie Chen",
"Xiaoxia Song",
"Changxia Yu",
"Hongyu Chen",
"Yan Zhao"
] |
https://doi.org/10.3390/jof10070496
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
39057381_p23
|
39057381
|
sec[4]/p[0]
|
5. Conclusions
| 4.394531 |
biomedical
|
Study
|
[
0.99951171875,
0.0003590583801269531,
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[
0.9990234375,
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FAD2 proteins from L. edodes contain three conserved histidine-rich regions (HXXXH, HXXHH, and HXXHH), which include eight histidine residues. Six homologous FAD2 polypeptide sequences were studied using MEGA 7.0 to elucidate the phylogenetic relationships. The distribution of introns was basically consistent with the phylogenetic tree classification results. Based on BLAST results, FAD2-4 and FAD2-6 were in the same clade with a 100% bootstrap value. The mutagenic heat-tolerant strain 18N44 had a lower linoleic acid content and lower FAD2 enzyme activity than wild-type strain 18, and the expression levels of the FAD2-2 and FAD2-3 genes under heat stress were significantly lower in strain 18N44 than in strain 18, indicating that FAD2-2 and FAD2-3 may play major roles in the synthesis of linoleic acid during heat stress. When L. edodes are subjected to heat stress, FAD2-2 and FAD2-3 may regulate gene expression levels to reduce the linoleic acid content for improved adaptation to heat stress. These data provide an essential basis for the in-depth study of unsaturated fatty acids, especially linoleic acid, and related proteins in L. edodes under heat stress and provide theoretical guidance for the breeding of new varieties of L. edodes at high temperatures.
|
[
"Huanling Yang",
"Jun Jiang",
"Mingjie Chen",
"Xiaoxia Song",
"Changxia Yu",
"Hongyu Chen",
"Yan Zhao"
] |
https://doi.org/10.3390/jof10070496
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999995 |
PMC11277958_p0
|
PMC11277958
|
sec[0]/p[0]
|
1. Introduction
| 4.117188 |
biomedical
|
Review
|
[
0.9970703125,
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[
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Idiopathic pulmonary fibrosis (IPF) is characterized as a lung disease of unknown cause that worsens progressively, resulting in mortality . Considering the prognosis, patients with IPF have a median survival rate of 2.5–3.5 years. Moreover, the 5-year survival rate of patients with IPF ranges from 20 to 40%. Irreversible and chronic progression are typical characteristics of IPF. The clinical course of IPF can vary from a slow progressive course for many months to years to a rapid, progressive course accompanied by an abrupt exacerbation of pulmonary symptoms and deteriorating lung function.
|
[
"Jeongeun Hwang",
"Hakyoung Kim",
"Sun Myung Kim",
"Dae Sik Yang"
] |
https://doi.org/10.3390/life14070897
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11277958_p1
|
PMC11277958
|
sec[0]/p[1]
|
1. Introduction
| 3.943359 |
biomedical
|
Study
|
[
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[
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] |
In particular, for patients with non-small-cell lung cancer (NSCLC) who have underlying IPF , cancer treatment, which includes radiotherapy, surgery, and chemotherapy, can result in substantial treatment-related complications. Among these, IPF has the potential to cause fatal pulmonary toxicity after radiotherapy and increase the morbidity and mortality of NSCLC patients .
|
[
"Jeongeun Hwang",
"Hakyoung Kim",
"Sun Myung Kim",
"Dae Sik Yang"
] |
https://doi.org/10.3390/life14070897
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999995 |
PMC11277958_p2
|
PMC11277958
|
sec[0]/p[2]
|
1. Introduction
| 3.751953 |
biomedical
|
Review
|
[
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[
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Currently, no drugs are available for treating IPF . Only two antifibrotic drugs, pirfenidone and nintedanib, have been approved. However, these drugs only slow the rate of fibrosis or scarring in the lungs and play a limited role in preventing rapid exacerbations of the disease . Recently, efforts have been undertaken to actively administer antifibrotic and anti-inflammatory drugs, such as Pirfenidone (Pirespa ® ), to patients diagnosed with IPF.
|
[
"Jeongeun Hwang",
"Hakyoung Kim",
"Sun Myung Kim",
"Dae Sik Yang"
] |
https://doi.org/10.3390/life14070897
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11277958_p3
|
PMC11277958
|
sec[0]/p[3]
|
1. Introduction
| 4.140625 |
biomedical
|
Study
|
[
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[
0.9990234375,
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In this context, we aimed to develop imaging complexity biomarkers to predict the incidence of severe pulmonary toxicity in patients with NSCLC who have underlying IPF and are treated with radiotherapy. Patients with chronic obstructive pulmonary disease (COPD) presenting with lower morphometric complexity in their lung parenchyma had poor prognoses . However, whether the association found in patients with COPD also applies to NSCLC patients with IPF undergoing radiotherapy is yet to be determined. In a previous study , box-counting fractal dimension measurements represented a morphological aspect of the parenchymal integrity of the lung. Assuming an analogy to NSCLC patients with IPF, a lower risk of severe radiation pneumonitis may be expected in patients with higher parenchymal integrity in the lung, who would have higher morphometric complexity. We aimed to develop a methodology for measuring morphometric complexity in NSCLC patients with IPF undergoing radiotherapy and to establish a framework to utilize complexity measurements for the prognosis of severe radiation pneumonitis.
|
[
"Jeongeun Hwang",
"Hakyoung Kim",
"Sun Myung Kim",
"Dae Sik Yang"
] |
https://doi.org/10.3390/life14070897
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999999 |
PMC11277958_p4
|
PMC11277958
|
sec[1]/sec[0]/p[0]
|
2.1. Patients
| 3.882813 |
biomedical
|
Study
|
[
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[
0.99755859375,
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We retrospectively reviewed the medical records of 257 patients with NSCLC who underwent thoracic X-ray radiotherapy at the Korea University Guro Hospital between March 2018 and December 2022. All diagnoses of the underlying pulmonary diseases were confirmed by experienced pulmonologists (J.H.C.). Among them, patients with no underlying pulmonary disease other than IPF, such as COPD, and those lacking pulmonary function tests were excluded; 19 patients with underlying IPF were included in this study.
|
[
"Jeongeun Hwang",
"Hakyoung Kim",
"Sun Myung Kim",
"Dae Sik Yang"
] |
https://doi.org/10.3390/life14070897
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277958_p5
|
PMC11277958
|
sec[1]/sec[1]/p[0]
|
2.2. Diagnostic Scheme for Lung Cancer and IPF
| 4.234375 |
biomedical
|
Study
|
[
0.99755859375,
0.002040863037109375,
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[
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] |
Tumor assessment included documenting a complete medical history, physical examination, complete blood counts, chemistry profiles, pulmonary function test (PFT), chest radiography, computed tomography (CT) of the chest and upper abdomen, whole-body 18F-fluorodeoxyglucose positron emission tomography with CT (FDG-PET-CT), and magnetic resonance imaging of the brain as a routine staging work-up. PFT, including both spirometry and diffusion capacity, was performed before treatment. Detailed measurements included the following: (1) forced expiratory volume in 1 s (FEV1), (2) forced vital capacity (FVC), (3) ratio of the two volumes (FEV1/FVC), and (4) diffusing capacity of the lung for carbon monoxide (DLCO). The diagnosis of IPF is made based on the presence of a typical radiological pattern, which is a coarse reticulation with a honeycombing appearance in the peripheral and predominantly basal lung areas on high-resolution CT. Spirometry typically reveals a reduction in vital capacity and DLCO. The GAP model, which includes four baseline variables (sex, age, and two lung physiology variables, FVC and DLCO), was used for IPF staging .
|
[
"Jeongeun Hwang",
"Hakyoung Kim",
"Sun Myung Kim",
"Dae Sik Yang"
] |
https://doi.org/10.3390/life14070897
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999999 |
PMC11277958_p6
|
PMC11277958
|
sec[1]/sec[2]/p[0]
|
2.3. Treatment Scheme and Surveillance
| 4.03125 |
biomedical
|
Study
|
[
0.95654296875,
0.04278564453125,
0.0008912086486816406
] |
[
0.87109375,
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] |
Based on the institutional protocol, stereotactic ablative radiation therapy (SABR) with a total dose of 60 Gy in four fractions was administered to NSCLC patients with small-sized (≤4 cm) and peripherally located tumors. For patients who received intensity-modulated radiation therapy (IMRT), two different dose-fractionation schedules were planned to deliver 60 Gy in 20 fractions in the radiotherapy-alone group and 66/60 Gy in 30 fractions in the concurrent chemoradiotherapy group using the simultaneous integrated boost technique.
|
[
"Jeongeun Hwang",
"Hakyoung Kim",
"Sun Myung Kim",
"Dae Sik Yang"
] |
https://doi.org/10.3390/life14070897
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999999 |
PMC11277958_p7
|
PMC11277958
|
sec[1]/sec[2]/p[1]
|
2.3. Treatment Scheme and Surveillance
| 4.019531 |
biomedical
|
Study
|
[
0.986328125,
0.0131683349609375,
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] |
[
0.8330078125,
0.1610107421875,
0.0028896331787109375,
0.0032291412353515625
] |
For target delineation of lung and mediastinal nodal lesions in IMRT planning, the gross tumor volume (GTV) was delineated under the lung and mediastinal window settings. The internal target volume (ITV) was delineated following four-dimensional CT with special regard to the patient’s respiratory motion. The clinical target volume (CTV) was generated with a 5 mm expansion of the GTV-ITV in all directions and then modified according to the adjacent normal anatomic structures. The planning target volume (PTV) was generated with a 5 mm expansion of the CTV. The prescription guideline was to deliver at least 97% of the prescribed dose to 95% of the PTV. The minimum and maximum doses to 1cc of PTV were 95% and 107%, respectively.
|
[
"Jeongeun Hwang",
"Hakyoung Kim",
"Sun Myung Kim",
"Dae Sik Yang"
] |
https://doi.org/10.3390/life14070897
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11277958_p8
|
PMC11277958
|
sec[1]/sec[2]/p[2]
|
2.3. Treatment Scheme and Surveillance
| 4.011719 |
biomedical
|
Study
|
[
0.984375,
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] |
[
0.806640625,
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] |
For target delineation of lung lesions in SBRT planning, the GTV was delineated under the lung window settings. The GTV-ITV was delineated following four-dimensional CT with special regard to the patient’s respiratory motion. The PTV was generated with a 5 mm expansion of the GTV-ITV. The prescription guideline was that 95% of PTV should be covered by prescription dose. The percentage lung volume that received ≥20 Gy was to be kept ≤35%, and the mean lung dose was ≤20 Gy. The maximum doses to the spinal cord and esophagus were not to exceed 45 Gy and 60 Gy, respectively, satisfying the dose-volume constraints of normal organs.
|
[
"Jeongeun Hwang",
"Hakyoung Kim",
"Sun Myung Kim",
"Dae Sik Yang"
] |
https://doi.org/10.3390/life14070897
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277958_p9
|
PMC11277958
|
sec[1]/sec[2]/p[3]
|
2.3. Treatment Scheme and Surveillance
| 3.507813 |
biomedical
|
Study
|
[
0.8564453125,
0.142333984375,
0.001007080078125
] |
[
0.92529296875,
0.06488037109375,
0.0023479461669921875,
0.00763702392578125
] |
Physical examination, blood tests, chest CT, and/or PET-CT were performed every 3 months for 2 years after radiotherapy and then every 6 months thereafter to detect disease progression during follow-up. Treatment-related complications were evaluated using the Common Terminology Criteria for Adverse Events (version 4.03).
|
[
"Jeongeun Hwang",
"Hakyoung Kim",
"Sun Myung Kim",
"Dae Sik Yang"
] |
https://doi.org/10.3390/life14070897
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277958_p10
|
PMC11277958
|
sec[1]/sec[3]/p[0]
|
2.4. Morphometric Complexity Measurements
| 4.148438 |
biomedical
|
Study
|
[
0.99951171875,
0.00030350685119628906,
0.00018405914306640625
] |
[
0.99951171875,
0.0002505779266357422,
0.0003590583801269531,
0.00007194280624389648
] |
To quantify the morphometric complexity of the lung parenchyma, box-counting fractal dimensions and lacunarity analyses were performed on a pre-radiotherapy-simulated chest CT scan. The model name is Canon’s Aquilion Lightning 80 (KV-CT, DLP (mGy) effective dose). In radiation treatment planning, IMRT planning used 6 MV energy, and SBRT planning used 6 FFF energy. Figure 1 shows the process and the morphometric analysis schema used in this study. Binary masks of intact lung parenchyma were defined as normal attenuation regions at >−950 HU and ≤−700 HU. An in-house box-counting fractal analysis tool was built according to the algorithm suggested by Grassberger and Ott et al. using MATLAB release 2022a (MathWorks Inc., Natick, MA, USA), with a higher dimension implying greater spatial filling. In brief, the number of imaginary cubes with sizes of 2, 4, 8, 16, and 32 voxel lengths needed to cover the normal attenuation region mask was counted, and a logarithmic regression was performed to estimate the power-law exponent, as in Formula (1): (1) F D b o x M ∝ log N ( ε ) log ( 1 ε ) where M is the 3D mask of the normal attenuation region, ε is the size of cubes, and N ( ε ) is the number of size ε cubes needed to cover the mask.
|
[
"Jeongeun Hwang",
"Hakyoung Kim",
"Sun Myung Kim",
"Dae Sik Yang"
] |
https://doi.org/10.3390/life14070897
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999994 |
PMC11277958_p11
|
PMC11277958
|
sec[1]/sec[3]/p[1]
|
2.4. Morphometric Complexity Measurements
| 4.113281 |
biomedical
|
Study
|
[
0.994140625,
0.00021123886108398438,
0.005489349365234375
] |
[
0.9619140625,
0.03680419921875,
0.0010232925415039062,
0.00012350082397460938
] |
Lacunarity is another measure of spatial heterogeneity but differs from the fractal dimension in that it measures rotation invariance . Lacunarity analysis also utilizes a box-counting method, in which the probability density of pixels belonging to the mask is counted within each box size. Formula (2) shows how a lacunarity Λ is calculated: (2) Λ = σ ε , g μ ε , g 2 where σ ε,g stands for the standard deviation of box-size ε and orientation g , μ ε,g is for the average . A higher lacunarity measurement denotes higher rotational variance and a more heterogeneous spatial distribution of the normal attenuation region mask .
|
[
"Jeongeun Hwang",
"Hakyoung Kim",
"Sun Myung Kim",
"Dae Sik Yang"
] |
https://doi.org/10.3390/life14070897
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11277958_p12
|
PMC11277958
|
sec[1]/sec[4]/p[0]
|
2.5. Statistical Analyses
| 4.054688 |
biomedical
|
Study
|
[
0.99951171875,
0.0004124641418457031,
0.0001709461212158203
] |
[
0.9990234375,
0.0003902912139892578,
0.00043201446533203125,
0.00007963180541992188
] |
The data are reported as numbers for categorical variables and medians for continuous variables. Time-to-event data on the occurrence of grade ≥ 3 radiation pneumonitis were used. Cox proportional hazard models were built to assess the hazards of morphometric complexity measures for radiation pneumonitis. Hazard ratios, 95% confidence intervals, and Harrell’s C-indices were calculated with or without adjustment for age, sex, smoking status, histology, and pre-radiotherapy DLCO. Proportional hazard assumptions were investigated by performing chi-square tests for the Shoenfeld residuals. Statistical significance was set at p < 0.05. All statistical analyses were performed using R statistics software version 4.3.1 (R Foundation for Statistical Computing, Vienna, Austria).
|
[
"Jeongeun Hwang",
"Hakyoung Kim",
"Sun Myung Kim",
"Dae Sik Yang"
] |
https://doi.org/10.3390/life14070897
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11277958_p13
|
PMC11277958
|
sec[2]/sec[0]/p[0]
|
3.1. Clinical Characteristics
| 3.982422 |
biomedical
|
Study
|
[
0.9765625,
0.0229034423828125,
0.0004756450653076172
] |
[
0.99462890625,
0.003307342529296875,
0.0006051063537597656,
0.001651763916015625
] |
Table 1 summarizes the clinical characteristics of the patients. The median age of the study population was 74 years (range, 53–86 years). Most patients were men (94.7%) and current or ex-smokers (89.5%). Prior to the initiation of radiation therapy, 50% of the patients with IPF were using anti-fibrotic medications. Most patients showed impaired pulmonary function with a DLCO of less than 60% (73.7%). Regarding the radiotherapy technique, 13 (68.4%) and 6 (31.6%) patients were treated with IMRT and SABR, respectively.
|
[
"Jeongeun Hwang",
"Hakyoung Kim",
"Sun Myung Kim",
"Dae Sik Yang"
] |
https://doi.org/10.3390/life14070897
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999999 |
PMC11277958_p14
|
PMC11277958
|
sec[2]/sec[1]/p[0]
|
3.2. Treatment-Related Complications
| 4.082031 |
biomedical
|
Study
|
[
0.7138671875,
0.28466796875,
0.0012578964233398438
] |
[
0.84814453125,
0.070068359375,
0.004222869873046875,
0.0777587890625
] |
The incidence of grade 3 or higher radiation pneumonitis was 42.1% (8/19) in patients with IPF, including one case of grade 5 radiation pneumonitis. In the remaining patient group excluding IPF, 17 out of 238 patients (7.1%) experienced grade 3 or higher radiation pneumonitis. Grade 5 complications were reported in a male patient who is a current smoker with underlying chronic kidney disease. In addition, the patient showed impaired pulmonary function (pre-radiotherapy DLCO: 40%), and no anti-fibrotic medication was taken. The patient was treated with definitive radiotherapy alone at a total dose of 60 Gy in 20 fractions using the IMRT technique. Severe radiation pneumonitis occurred 4 months after the completion of IMRT. The results of pulmonary function tests performed at that time were worse (post-radiotherapy DLCO, 31%). After hospitalization, the patient died of severe radiation pneumonitis and an exacerbation of the underlying disease, IPF, despite intensive treatment with steroids and mechanical ventilation.
|
[
"Jeongeun Hwang",
"Hakyoung Kim",
"Sun Myung Kim",
"Dae Sik Yang"
] |
https://doi.org/10.3390/life14070897
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277958_p15
|
PMC11277958
|
sec[2]/sec[2]/p[0]
|
3.3. Morphometric Complexity Analysis
| 4.113281 |
biomedical
|
Study
|
[
0.9990234375,
0.0006785392761230469,
0.0002455711364746094
] |
[
0.99951171875,
0.0002359151840209961,
0.0003230571746826172,
0.00009399652481079102
] |
Box-counting fractal dimensions and lacunarity analyses were performed on all patients’ pre-radiotherapy chest CT scans. All patients were dichotomized at median values. The hazards of lower-than-median fractal dimension or lacunarity for grade ≥ 3 events were estimated by building Cox proportional hazard models with and without adjustment. The adjusted models included age, sex, smoking status, histology, and DLCO. Chi-square tests for the Schoenfeld residuals of each model showed no significant violation of the proportional hazards assumption. In addition, log-rank tests were performed on the incidence curves of the lower- and higher-than-median groups. Table 2 shows the hazard ratios and their 95% confidence intervals, p -values, Harrell’s C-indices, and p -values of the log-rank tests. After adjusting for age, sex, smoking status, histology, and DLCO, eight patients with a lower fractal dimension showed a significantly higher hazard ratio of 7.755 (1.168–51.51) for grade ≥ 3 pneumonitis than those with a higher fractal dimension. Patients with lower lacunarity exhibited significantly lower hazards in all models, both with and without adjustments. The lower-than-median lacunarity group also showed significantly lower incidence curves for all models built in this study.
|
[
"Jeongeun Hwang",
"Hakyoung Kim",
"Sun Myung Kim",
"Dae Sik Yang"
] |
https://doi.org/10.3390/life14070897
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999995 |
PMC11277958_p16
|
PMC11277958
|
sec[2]/sec[2]/p[1]
|
3.3. Morphometric Complexity Analysis
| 3.945313 |
biomedical
|
Study
|
[
0.99951171875,
0.00029349327087402344,
0.0003437995910644531
] |
[
0.99951171875,
0.0003173351287841797,
0.00033593177795410156,
0.00005418062210083008
] |
We performed two alternative analyses sharing the same features and architects of models as previously described, except (1) by using grade ≥ 2 pneumonitis instead of grade ≥ 3 as outcome event definition or (2) by adjusting for GAP stage instead of age, sex, smoking status, histology, and DLCO in the multivariate regression model. All the alternative analyses qualitatively exhibited the same results as those of the previously described models.
|
[
"Jeongeun Hwang",
"Hakyoung Kim",
"Sun Myung Kim",
"Dae Sik Yang"
] |
https://doi.org/10.3390/life14070897
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999993 |
PMC11277958_p17
|
PMC11277958
|
sec[3]/p[0]
|
4. Discussion
| 4.117188 |
biomedical
|
Study
|
[
0.99951171875,
0.000377655029296875,
0.0002040863037109375
] |
[
0.99951171875,
0.00022029876708984375,
0.0004200935363769531,
0.00007855892181396484
] |
We attempted to identify CT morphometric complexity biomarkers representing normal lung tissue integrity in NSCLC patients who have underlying IPF, thereby associating them with the risk of severe radiation pneumonitis after radiotherapy. We adopted box-counting fractal dimension and lacunarity analyses. Both the fractal dimension and lacunarity are measures of morphometric complexity based on the box-counting method. The box-counting fractal dimension is a measure of the space-filling property, whereas lacunarity is a measure of rotation invariance. Fractal analysis has previously been used as a measure of lung parenchymal integrity in patients with COPD and is associated with survival . In that study, the fractal analysis was on binary masks of the normal attenuation area, which was voxels ≥−950 HU within the lung . The fractal dimension is more closely associated with COPD symptoms and survival than the volume fraction of the low attenuation region, owing to the lung inflation-level robustness of the box-counting method. Because our study included NSCLC patients with underlying IPF, we modified the identification of normal attenuation areas as >−950 HU and ≤−700 HU within the lung.
|
[
"Jeongeun Hwang",
"Hakyoung Kim",
"Sun Myung Kim",
"Dae Sik Yang"
] |
https://doi.org/10.3390/life14070897
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277958_p18
|
PMC11277958
|
sec[3]/p[1]
|
4. Discussion
| 4.183594 |
biomedical
|
Study
|
[
0.99951171875,
0.0004355907440185547,
0.0002028942108154297
] |
[
0.9990234375,
0.00028777122497558594,
0.0004372596740722656,
0.00010466575622558594
] |
In fractal dimension analysis, we found a marginal association between a fractal dimension and grade ≥ 3 pneumonitis and a significant association when adjusted for age, sex, smoking status, histology, and DLCO in a way that patients with higher fractal dimension values had less hazard than those with lower values. We observed significant associations between a lower lacunarity value and less grade ≥ 3 pneumonitis hazard in both crude and adjusted multivariate Cox-proportional hazard models . We speculate that these morphometric characteristics indicate better parenchymal integrity in the lungs. Intuitive interpretation of a box counting fractal dimension is a space-filling property, and that of lacunarity is a ‘gappiness,’ or rotation invariance . Airways and blood vessels in the lung are both tree structures, and they are expected to have high space-filling properties in a ‘healthy’ lung . The inherent tree structures of the airways and blood vessels in the lungs may have high lacunarity values because of the high rotation variance and gappiness of the tree structures. Alternatively, normal lung parenchyma excluding emphysematous regions (≤−950 HU) and fibrotic, consolidated regions (>−700 HU) with good integrity would also have high space-filling properties but would have less gaps and have rotationally homogeneous structures. The association was significant for lacunarity and marginal for the fractal dimension; the reason for this discrepancy is unclear. This may imply that lacunarity is a more appropriate imaging biomarker for prognosis in NSCLC patients with underlying IPF receiving radiotherapy; however, the relatively small sample size of 19 patients precludes this conclusion.
|
[
"Jeongeun Hwang",
"Hakyoung Kim",
"Sun Myung Kim",
"Dae Sik Yang"
] |
https://doi.org/10.3390/life14070897
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11277958_p19
|
PMC11277958
|
sec[3]/p[2]
|
4. Discussion
| 4.058594 |
biomedical
|
Study
|
[
0.99951171875,
0.00024390220642089844,
0.00016701221466064453
] |
[
0.99951171875,
0.00025463104248046875,
0.00028395652770996094,
0.00006175041198730469
] |
We developed a methodology for measuring morphometric complexity in NSCLC patients with IPF undergoing radiotherapy and established a framework to utilize box-counting fractal dimension and lacunarity measurements for the prognosis of severe radiation pneumonitis, showing significant associations between lower lacunarity and less hazard. The present study showed associations, so further investigations with more participants and different study designs are needed to understand the detailed mechanism of this association between morphometric complexity and radiation pneumonitis hazards or to identify causal inferences. IPF itself is a rare disease; based on the results of the analysis of 19 patients in this study, we plan to expand future research to all interstitial lung disease and COPD disease groups.
|
[
"Jeongeun Hwang",
"Hakyoung Kim",
"Sun Myung Kim",
"Dae Sik Yang"
] |
https://doi.org/10.3390/life14070897
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999995 |
PMC11277958_p20
|
PMC11277958
|
sec[4]/p[0]
|
5. Conclusions
| 3.980469 |
biomedical
|
Study
|
[
0.99951171875,
0.0002111196517944336,
0.00016057491302490234
] |
[
0.99853515625,
0.0009055137634277344,
0.00028204917907714844,
0.0000941157341003418
] |
We have devised a technique for quantifying morphometric complexity in NSCLC patients with IPF who are receiving radiotherapy and discovered lacunarity as a potential imaging biomarker for grade ≥ 3 pneumonitis.
|
[
"Jeongeun Hwang",
"Hakyoung Kim",
"Sun Myung Kim",
"Dae Sik Yang"
] |
https://doi.org/10.3390/life14070897
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
39057185_p0
|
39057185
|
sec[0]/sec[0]/p[0]
|
1.1. Religiosity and Intelligence
| 1.444336 |
other
|
Other
|
[
0.0159759521484375,
0.00055694580078125,
0.9833984375
] |
[
0.276611328125,
0.3837890625,
0.3369140625,
0.00274658203125
] |
Research about religiosity and intelligence associations goes back almost a century by now, with the first formal empirical studies published in 1928 . Since then, a plethora of corresponding reports have supported negative associations between religiosity and intelligence. Meta-analytical examinations have corroborated the robustness of this association , suggesting that this link generalizes across various moderators in terms of effect direction but appears to differ in terms of effect strength . A participant’s age has been argued to represent another potential cause of effect size variation as in older age, religiosity may have protective effects against cognitive decline . However, recent evidence does not support this idea .
|
[
"Florian Dürlinger",
"Thomas Goetz",
"Jakob Pietschnig"
] |
https://doi.org/10.3390/jintelligence12070065
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
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