The effect of incorporating different loadings of oil palm bio-ash nanoparticles from agriculture waste on the properties of phenol-formaldehyde resin was investigated in this study. The bio-ash filler was used to enhance the performance of phenol-formaldehyde nanocomposites. Phenol-formaldehyde resin filled with oil palm bio-ash nanoparticles was prepared via the in-situ polymerization process to produce nanocomposites. The transmission electron microscope and particle size analyzer result revealed that oil palm bio-ash nanoparticles had a spherical geometry of 90 nm. Furthermore, X-ray diffraction results confirmed the formation of crystalline structure in oil palm bio-ash nanoparticles and phenol-formaldehyde nanocomposites. The thermogravimetric analysis indicated that the presence of oil palm bio-ash nanoparticles enhanced the thermal stability of the nanocomposites. The presence of oil palm bio-ash nanoparticles with 1% loading in phenol-formaldehyde resin enhanced the internal bonding strength of plywood composites. The scanning electron microscope image revealed that phenol-formaldehyde nanocomposites morphology had better uniform distribution and dispersion with 1% oil palm bio-ash nanoparticle loading than other phenol-formaldehyde nanocomposites produced. The nanocomposite has potential use in the development of particle and panel board for industrial applications. All part of the oil palm is useful for domestic purposes. However, most oil palm plant parts are disposed of as waste biomass because of their abundance. The large production of palm oil by oil extraction in the palm oil mill has abundantly produced secondary waste, negatively impacting health due to environmental pollution . Most ofmosphere . The oilmosphere .Nanoparticles have been used as filers for improved physical and chemical strength, and thermal properties of polymers . NanoparIn thermoset polymers, phenol-formaldehyde (PF) resin is one of the most common formaldehyde-based resins, which provides outstanding adhesion performance, high-temperature resistance, flame resistance, and electric insulation. Thus, phenol-formaldehyde (PF) resins have been and are still being used extensively in the industry ,17. BesiDespite the advantages of phenol-formaldehyde resin, its major drawbacks prevent its widespread application. Some of the challenges attributed to PF resins are high brittleness and shrinkage. Improvement in the properties and performance of resin composite has been intensively investigated in recent years. It was proposed that the addition of a nanofiller can enhance its functional properties, such as permeability resistance, improved thermal stability, enhanced mechanical properties, and decreased the formaldehyde emission values . Some reThe suitability of oil palm bio-ash incorporated into phenolic adhesives is partly determined by chemical features involved in polymerization reactions. The two most important oil palm ash features are bonding with the phenolic hydroxyl and the main element composition in oil palm ash. Generally, the addition of fillers can enhance PF resin with specific properties. However, the addition of fillers sometimes leads to the degradation of the characteristics of polymers. However, the appearance of nanotechnology opens a new route for improving PF resin’s properties . To imprPF resin is noted for low internal bonding strength and thermal stability when used in panelboards ,30. The Oil palm bio-ash (OPB) was obtained from United Oil Palm Mill, Penang, Malaysia. The bio-waste from the hopper section, also known as secondary waste in the palm oil mill, was a suitable candidate due to its particle size, which is more effortless to convert from micron to nano-size materials. The polymeric matrix used was phenol-formaldehyde (PF) resin, a resol type used specifically for wood-based applications. The resin was obtained from Hexion Specialty Chemicals Sdn. Bhd., Penang, Malaysia.The experimental design for the preparation of oil palm ash nanoparticles was adopted based on a previous study by  on the TThe influence of the functional groups in the interaction between PF resin structure and OPA composition was investigated using the Fourier Transform Irradiation (FT-IR). The thermal stability of PF nanocomposites was evaluated using thermogravimetric (TGA). An X-ray Diffraction analyzer (XRD) was used to examine the crystalline structure in PF nanocomposites. Morphological analysis was performed to investigate the dispersion and distribution of OPB nanoparticles in PF resin nanocomposites.The particle size analysis of the initial materials and milled powders was measured with a Malvern Mastersizer  scirocco 2000 by dynamic light scattering measurements. In each measurement, the detector and laser were aligned, and the background was calibrated. Size distribution was quantified as the relative volume of particles in size bands presented as size distribution curves . Particle size distribution was described according to D-Values , corresponding to 10%, 50%, and 90% of the cumulative mass.Transmission electron microscopy (TEM) was carried out with an EFTEM Libra . The OPB nanoparticles were oven-dried before using the TEM to characterize the size and morphology of the particles. The OPB nanoparticles were prepared in acetone and dispersed with an ultrasonicator for 10 min. TEM analysis samples were obtained by placing a drop of colloidal dispersion containing OPB nanoparticles onto a carbon-coated copper grid. Embedded OPB nanoparticles were air-dried at room temperature before being examined under a TEM instrument under control conditions.In this study, the PF nanocomposites were prepared with 0%, 1%, 2%, 3%, 4%, and 5% of OPB nanoparticles . The size of OPB used in the nanocomposite preparation was 91 nm (average sizes). The OPA nanoparticle loading was limited to 5% because of void and agglomeration in the cured nanocomposites. These problems could lead to a reduction in the performance of PF nanocomposites . Thus, tThe preparation of neat PF resin involves pouring PF resin without OPB nanoparticles into the mould at room temperature. Afterwards, it was heated at 150 °C to polymerize the PF resin. Then, the PF resin was mixed with the desired amount  of OPB nanoparticles at room temperature for 30 min using a mechanical stirrer at 800 rpm. This approach afforded the flexibility in exercising independent control over reinforcement material and reinforcement geometry  . Each mi−1 and 4000 cm−1 for the analysis.Fourier transform infrared (FT-IR) spectroscopy was performed using a Shimadzu  FT-IR instrument with the KBr pellet technique. The PF-filled OPB nanoparticles nanocomposites and Potassium Bromide (KBr) were dried accordingly before disk preparation. In disk preparation using the mortar, the OPB nanoparticles were pounded with KBr until the homogenized mixture was formed. Then, the mixture was pressed until 500 MPa to obtain a disk form. The disk was carefully placed into the Shimadzu FT-IR instrument for FT-IR analysis. The FT-IR spectrum was set between 400 cmTGA was carried out using Mettler Toledo  Model TGA/DSC simultaneous analyzer with a heating rate of 20 °C/min from room temperature up to 900 °C under nitrogen atmosphere. Investigation of PF nanocomposites filled with OPB nanoparticles thermal stability was analyzed in powder form using approximately 5–7 mg/analysis.Wide-angle X-ray diffraction (XRD) was carried out to identify changes in the PF resins’ crystalline structure with and without OPB nanoparticles. X-ray diffractograms were obtained using a Philips  PW1050 X-pert diffractometer, Cu-Ka1 radiation, at 40 kV, 25 Ma, and λ = 1.54 Å. The diffractograms were scanned from 2.5° to 90° (2θ) in steps of 0.02° using a scanning rate of 0.5 °C/min.2 before being cold-pressed for 10 min. The cold press method is intended to develop consolidation between the surfaces of the raw materials. After that, they were then hot-pressed for 30 min. at a temperature of 150 °C, at approximately 200 bars (3000 psi) pressure. Finally, the plywood composites were left for cold pressing for 30 min before being cut into a standard dimension for internal bond strength.The internal bonding strength of the PF nanocomposite was measured by using it as a binder in plywood. The plywood composites were prepared by using hand lay-up techniques for making a test sample. The schematic layering pattern of the 5-plywood veneer was shown in The density profile of the samples along the thickness of panels was determined using Density Profiler Grecon model DA-X . The samples with a dimension of 50 × 50 × 10 mm were cut and maintained in a chamber at ambient temperature (25 ± 3 °C) and relative humidity of 30% (±2%) before testing. During scanning, the samples were inserted into the cassette holder for each batch scan and analyzed every 0.025 mm/s. In each case, the density profiles of the five samples were tested, and the average value tabulated.P′) was measured at the time of failing force (breaking load of perpendicular tensile strength to the board). The sample was produced in triplicate, and standard deviation was used to measure the significant difference of the result.IB strength was determined according to Japanese standards (JIS) using an Instron Testing Machine Model 5582 . In this test, the length, width, and thicknesses of the samples were measured and recorded. The test sample was glued with hot melt adhesive to the two specimen holders, inserted into the testing equipment, and left for 24 h. A tension load of 2 mm/min was applied vertically to the sample face and the maximum load  instrument was used to examine the morphological structure of the images of ground OPB and PF nanocomposite-filled OPB nanoparticles. A thin section of the sample was mounted onto an aluminium stub and sputter-coated with gold to enhance the conductivity of the test samples before the morphological examination. The FESEM micrographs were obtained under conventional secondary electron imaging conditions with an acceleration voltage of 5 kV. The EDX spectroscopy was recorded for all samples to investigate specific elements of phenolic nanocomposites.The morphology, particle distribution, and elemental composition of oil palm bio-ash (OPB) nanoparticles are shown in Results of OPB nanoparticles morphology and particle size distribution after the ball milling process are shown in 2) was influenced by their concentration, band structure, and density. Besides, a previous study by Omar [ϴposition, and the shape of X-ray spectra. In addition, an observation by Alsubari, Shafigh [2O3). However, it was suggested that impurities incapable of developing high peak intensity resulted in a crystalline structure due to the impurities attributed to foreign grains.X-ray Diffraction (XRD) testing is done to get diffraction patterns of the crystalline structures of the OPB nanoparticles. The X-ray diffraction (XRD) spectroscopy of OPB nanoparticles is shown in  by Omar  also con Shafigh  found th−1, probably due to the reaction between OPB nanoparticles and phenol-formaldehyde at various times. The rise in peak intensity as the percentage of OPB nanoparticle increased indicating a growth of the Si-OH bond. The absorption bands observed at 3400 to 3500 cm−1 were stretching vibration of -OH and silanol hydroxyl groups of silica inside the OPB [−1 was reported by Ooi, Ismail [A comparison of the FT-IR spectrum of regular phenol-formaldehyde (PF) resin, OPB nanoparticle, and PF nanocomposite-filled OPB nanoparticles (1–5%) is shown in  the OPB ,39. A hy−1. During the ball milling process to convert raw OPB to nano-size OPB, the breakdown of the silica structure leading to the formation of silanol resulted in the hydroxyl derivative of silane. The increase in the intensity may be due to the higher volume of –OH and a silanol hydroxyl group from OPB nanoparticles associated with phenolic hydroxyl bonds. The mechanism of hydrogen bonding between silica and phenol-formaldehyde resin in PF nanocomposite is shown in These findings also agree with the observations by Paul, Satpathy  during t−1. The peak corresponds to the typical stretching of the C=O bond. For ordinary PF Resin, the peak at 1664 cm−1 shows lower stretching vibration C=O and the relative strength of the peak lower, compared with PF nanocomposite-filled OPB nanoparticles. The peak spawned for PF nanocomposite-filled OPB nanoparticles may probably be attributed to a reaction between elements of OPB nanoparticles such as silica and a phenol hydroxyl group from PF resin. Research by Chen Li et al. [−1, and 3500 cm−1 were attributed to the stretching of –OH and bending vibration of O-H-O bonding. Usually, these bands were incorporated with water and water did not exist in OPB nanoparticles. This behaviour indicated a polymerization and transformation formation of –OH and O-H-O bonding in the nanocomposite [The FT-IR spectra also revealed that once the OPB nanoparticles are incorporated with phenolic hydroxyl molecules, the bonding’s impact produces significant band broadening and stabilizes the peak intensity. The broadening peak and steady absorption frequency indicate asymmetric stretching and strength of the hydrogen bonding with the most energy and instability. In certain circumstances, the intermolecular hydrogen bonds between neighbouring molecules form a stable dimeric structure, a highly characteristic one, and lower mean absorption frequency . The prei et al.  and Vijai et al.  indicateomposite .Thermogravimetric (TG) and derivatives thermogravimetric (DTG) of neat PF and PF nanocomposite are shown in Particularly, the PF resin-filled OPB nanoparticles with different loadings showed a similar trend of thermolysis behaviour. This behaviour is attributed to the cross-linkage of the incorporated OPB nanoparticles with PF resin. In the first stage of weight loss, it was found that there was a small exothermic reaction in the range of 80–120 °C. This could be an evaporation process derived from water and formaldehyde that evolved due to increased temperature during the analysis . PF resiThe results of the thermal analysis via TGA thermograms are expressed in The second stage degradation of nanocomposites takes place at 290 °C up to 321 °C. From Moreover, due to the effect of heat retardant of OPB nanoparticles, more energy is required during the degradation process, therefore enhancing the thermal stability of the nanocomposites ,51. MeanMeanwhile, the final degradation temperature (FDT) of nanocomposite-filled 1% OPB nanoparticles increased from 506–516 °C, possibly incorporating OPB nanoparticles with PF polymer chains. With the lower loading of OPB nanoparticles, there was a significant interaction between PF polymer chains and OPB nanoparticles, possibly impeding the oxidation of polymer chains and increasing the nanocomposites’ final degradation temperature. However, with the increase of OPB nanoparticle loading in nanocomposites, the final degradation temperature gradually decreased and became a comparable value after that. The decrease of FDT could be from the non-uniform dispersion of OPB nanoparticles throughout the PF matrix . This beThe last stage of the degradation process, which is preferably called the carbonization zone, occurs at 700 °C. However, with a vast relative surface area of OPB nanoparticles, there was still great interaction between OPB nanoparticle components with PF molecular chains, which enhanced the thermal stability of nanocomposites compared to neat PF composite. Compared with the neat PF nanocomposite, degradation temperatures were observed to be higher. This phenomenon proved that any filler, either micron or nano size, would play a significant role in acting as thermal insulation to improve the poor thermal stability of the PF matrix. Based on The X-ray Diffraction (XRD) spectroscopy PF nanocomposite-filled OPB nanoparticles compared to neat PF resin are shown in The broadening (width) of the XRD spectrum indicated the effect of lattice strain. In this case, OPB nanoparticle in PF nanocomposites, probably OPB nanoparticle, has formed a bigger crystal size, resulting in less of a broad peak and certainly developing a sharp peak, as presented in The density profile of plywood composites and the relationship of the average density of plywood composites with internal bonding strength in different loading of OPB nanoparticles are shown in 3 compared to IB of plywood composites applied with OPB nanoparticles. In general, the IB of plywood composites tends to increase with increasing plywood composite density. From the results, it can also be seen that the application of PF-filled OPB nanoparticles on the veneer did not only improve the bonding quality but also slightly increase the density of the plywood composites. PF resin-filled OPB nanoparticle loading could be attributed to the interpenetrated network, which caused the OPB nanoparticles to fill in the plywood porosity veneer during the curing process.The relationship between density and internal bond (IB) of the plywood composite was displayed in Meanwhile, the higher content of OPB nanoparticles in PF resins affects the interface bonding between PF resins and layering panels. The possible reason for the enhanced IB of the plywood composites was that reinforcement with OPB nanoparticles improved the crosslink density of the PF resin, which helped the PF resin to be cured throughout the panel . The difThe morphological properties of neat PF and PF nanocomposite-filled FESEM investigated OPB nanoparticles are shown in Meanwhile, with 2% OPA loading, the behaviour of the OPB nanoparticles tends to agglomerate due to an increase of surface energy between themselves. The homogenous dispersion of OPB nanoparticles in PF nanocomposites without an obvious aggregate phase separation could be seen in Based on The improved performance of PF nanocomposites has potential use in the wood-based industry. This work opened a gate to utilise agriculture waste transformation into nanomaterials incorporated with adhesives or resin to produce low-cost and environmentally-friendly products. Different products can be generated using different nanoparticle sizes. A further study on the effect of nanoparticle size on the properties of PF nanocomposite can be conducted.The preparation and incorporation of different percentage loading of OPB nanoparticle as a filler in resin was successfully conducted without miscibility enhancement. The morphology of the nanocomposite confirmed the dispersion of nanoparticles in the PF resin nanocomposite. The properties of the resulting nanocomposites show improved internal bonding strength with nanoparticle addition, compared with the neat resin. In addition, the thermal stability of the nanocomposite was observed to increase due to the incorporation of nanoparticles. The enhancement in its properties was probably due to forming a bond between the matrix and the filler, as shown by the FT-IT studies. Furthermore, the crystallinity of the nanoparticles is shown in the Xrd result. The PF nanocomposites’ improved performance in this study could lead to improved wood-based industry and multifunctional products for various applications. The use of agricultural waste in functional nanomaterials could reduce the pollution problem and the cost of production of environmentally friendly products.


Lateral tunnel junctions are fundamental building blocks for molecular electronics and novel sensors, but current fabrication approaches achieve device yields below 10%, which limits their appeal for circuit integration and large-scale application. We here demonstrate a new approach to reliably form nanometer-sized gaps between electrodes with high precision and unprecedented control. This advance in nanogap production is enabled by the unique properties of 2D materials-based contacts. The large difference in reactivity of 2D materials’ edges compared to their basal plane results in a sequential removal of atoms from the contact perimeter. The resulting trimming of exposed graphene edges in a remote hydrogen plasma proceeds at speeds of less than 1 nm per minute, permitting accurate control of the nanogap dimension through the etching process. Carrier transport measurements reveal the high quality of the nanogap, thus-produced tunnel junctions with a 97% yield rate, which represents a tenfold increase in productivity compared to previous reports. Moreover, 70% of tunnel junctions fall within a nanogap range of only 0.5 nm, representing an unprecedented uniformity in dimension. The presented edge-trimming approach enables the conformal narrowing of gaps and produces novel one-dimensional nano-trench geometries that can sustain larger tunneling currents than conventional 0D nano-junctions. Finally, the potential of our approach for future electronics was demonstrated by the realization of an atom-based memory. Carrier transport through atomically thin barriers proceeds by quantum mechanical tunneling, and the dependence of the tunneling current on barrier dimension and electrostatics are the foundation for scanning tunneling microscopes , tunneliTo realize electrodes with atomic-scale lateral gaps, different strategies have been reported. Nanogaps have been formed by focused ion beam (FIB) milling , feedbacOne common challenge for all approaches is the scalable fabrication of identical devices due to the high sensitivity of nanogap performance on minute variations in patterning accuracy, pre-produced electrode dimensions, and environmental effects. This issue is exemplified in the low success rate of nanogap formation even under seemingly identical conditions. Thus far, the highest production yields of lateral tunneling junctions have been 7% , and sigA potential solution to these challenges lies in the recent discovery of 2D materials ,16,17,18We here report the fabrication of lateral nanogaps with atomic dimensions in large arrays with yield rates of 97%. The selective plasma-assisted removal of atoms from the edge of 2D materials permitted the trimming with atomic precision, enabling unprecedented control over the nanogap dimension. The conformal removal process furthermore enabled the formation of one-dimensional nanogaps that exhibit larger tunneling currents than conventional 0D constrictions. Carrier transport reveals that electrons traverse the thus formed nanogaps exclusively through direct tunneling, as evidenced by temperature-independent currents. Finally, we demonstrate the ability to produce arrays of lateral tunnel junctions with a precision of 0.5 nm over centimeter-scale and apply our advance to atomic-scale memory.Lateral tunneling junctions were fabricated from graphene, a two-dimensional carbon allotrope. Graphene was chosen due to the large tunneling probability that originates from its small effective mass . Moreove2 wafers. Edges were introduced into the graphene by lithographically patterning photoresist and removing the unprotected graphene through oxygen exposure. Subsequent deposition of metal contacts  using the same photoresist patterns results in the self-aligned formation of 1D edge contacts to the 2D material [We present a novel approach to producing atomic-scale nanogaps by combining bottom-up and top-down patterning approaches. First, graphene was synthesized by chemical vapor deposition on copper foil following previous reports ,25 and tmaterial . After lThe thus-prepared graphene/Au edge contact was then exposed to a remote hydrogen plasma with a separation of 40 cm between the plasma source and the substrate. A continuous hydrogen flow of 5 sccm at a chamber pressure of 3 mTorr was maintained to generate a flux of ions from the plasma source to the substrate b. This pWe observe a sharp interface between the Au contact and the graphene by scanning electron microscopy d and proCharacterizing nanogaps at the interface between the contact and graphene is a significant challenge to imaging techniques. Atomic force microscopy (AFM) is an established technique to study nanostructures, but it cannot image the edge of the contact as the lateral extend of the AFM tip is larger than the nanogap. Additional challenges in the sensitivity of the amplitude feedback lead to a significant overestimation of the gap extent a and canAfter the etching process, we conduct electrical transport measurements and observe a non-linear trend of current with voltage b. SeveraAccording to Equation (1), a linear trend in the FN-plot is expected, and we indeed observe linearity when graphing ln(. ln(1V) c. This r results  and a ba results ,33. Our After establishing the properties of the tunneling junction, we demonstrate the fine tunability of the nanogap width through control of the etching process. We extract the gap dimensions from different samples that were etched for various times using the aforementioned approach b. We finMoreover, different etching durations are shown to produce an increase in gap size, and the trend agrees with previous observations of the graphene-edge etch rate in hydrogen plasma of 0.27 nm/min [The uniformity of the nanogap size along the 1D nano-trench was investigated by comparing the tunneling current at a similar gap size but different nano-trench lengths c. We fin2 Si/SiO2 substrate to emulate large-scale integration. To demonstrate the scalability of our approach, we produced devices at wafer-scale. A total of 30 lateral tunneling devices were distributed across a 2.0 × 3.0 cmThe variability of the remaining devices is explained by differences in their tunneling gap, and we find that all of these 30 devices (97%) exhibit gaps between 0 and 3 nm. The demonstrated device yield a significant improvement over previous arrays where only seven out of 86 break junctions fell in the same gap range . MoreoveOur results not only enable the scalable fabrication of electrodes that are suitable for molecular electronic devices but could open up new applications. The ability to form atomic-scale gaps could, for example, increase the density of memory devices. Current high-density resistive memory devices that rely on the one-diode-one-resistor could be implemented in a single tunneling device by exploiting the non-linearity and tunable electrostatics of tunneling junctions . MoreoveIn conclusion, we have demonstrated a new method to reliably generate lateral tunneling junctions that exhibit atomic size nanogaps at unprecedented precision and scale. 2D material edge contacts were selectively trimmed to produce novel 1D nano-trenches whose width could be finely controlled by the etching process. Carrier transport measurements indicate the high quality of these structures and superior uniformity of their dimensions across large samples compared to traditional patterning approaches. Our results open up new applications in electronic devices, sensing, and atomic-scale information storage.


EGFR is linked with oral cancer. Therefore, it is of interest document the molecular docking analysis of compounds from Andrographis paniculata with EGFR. Data shows the binding features of five compounds 14- acetylandrographolide, andrograpanin, andrographolide,isoandrographolide and neoandrographolide from Andrographis paniculata with EGFR for further consideration. Oral squamous cell carcinoma is the most predominant malignant epithelial neoplasm in the oral cavity . Oral sqThe target structure of EGFR with PDB ID: 2JIT was obtained from the Protein Data Bank. It belongs to the classification of Homo sapiens transferase proteins. The three-dimensional structure was determined using X-ray diffraction process. The recovered proteinstructure was prepared using AutoDock Methods. Water molecules and all non-standard residues have been excluded from the initial structure. Then, all missing hydrogens and kollman charges have been applied to the device; the prepared protein receptor was then savedas a pdbqt format and stored directly in the PyRx workspace directories.Ten chemical components of Andrographis paniculata have been obtained from the Pubchem database (Table 1 - see PDF). In this analysis, pdb coordinates were used for all hydrogen output formats. The charges were further repaired by inserting partial gasteigercharges and then push the autodock. Then the structure of the compounds was opened on PyRx by clicking on Load Molecule and making ligand.Many docking algorithms becomes capable of constructing a wide range of possible structures, so they still need a means to score each structure to categories those of greatest interest. In the present study, the docking process was carried using PyRx 0.8 withthe Autodock Vina method using the Lamrkian genetic algorithm as the score function was completed . PossessIn this analysis, the ligand-protein molecular docking simulation was used for preliminary investigation and confirmation of potential compounds for the selected EGFR target. The analysis of the effective docked ligands against the selected target demonstratedthe binding mode of the compounds involved in this research and verified their function as anti-cancer agents. The binding energy of the drug – protein (receptor) interactions is important to explain how well the drug binds to the target macromolecule. The residuesthat participated in the formation of hydrogen bonds inside the active binding site region highlighted the importance of these residues to the reported binding energy with respect to the hit found against the EGFR target protein. The resulting hypothesis may be anincredible starting point for the creation of some new pathways as potential EGFR inhibitors that improve affinity as well as intrinsic function. The results of this work show that powerful analytical tools are capable of recognizing potential ligands. The use ofcomputational methods in the discovery and creation of drugs could be used to minimize time and minimize the work of a medical chemist. The molecular docking simulation of the phytochemicals provided by Andrographis paniculata reveals that perhaps the plant constituentsall have comparatively high binding energy and therefore low binding (Table 2 - see PDF). Out of ten compounds, best five compounds  were selected based on scoringparameters.The 14-acetylandrographolide bound to the target exhibited a fitness score of -8.0 and interacted with the active site residues ASN-700, ASP-761, TYR-764 & LYS-949. The compound andrographolide exhibited a fitness score of -7.1 and interacted with the residuesLYS-949 & ARG-977 at the active site. This shows good interaction and efficient score (Table 2 - see PDF). The compounds Isoandrographolide showed the good binding affinity with the binding score of -8.1 and formed the two hydrogen bond interactions with EGFRprotein through ASP-761 & ARG-977. Likewise Neoandrographolide and Andrograpanin showed the strongest binding score -7.0 & 6.8 respectively. In this Neoandrographolide formed three hydrogen bonds with the amino acids ASP-761, LYS-949 & LYS-960 andAndrograpanin showed the two hydrogen bonds with EGFR through LYS-949 & ARG-977. Selected five docked complexes showed the hydrogen bonds distance below 3 Å it confirmed that all the compounds formed the stable complex with EGFR. Analysis of these complexesalso revealed that all most all the compounds formed the hydrogen with the amino acids LYS-949 & ARG-977 . So, theData shows the binding features of five compounds 14-acetylandrographolide, andrograpanin, andrographolide, isoandrographolide and neoandrographolide from Andrographis paniculata with EGFR for further consideration.


Neurotrophic factors (NTFs) are small secreted proteins that support the development, maturation and survival of neurons. NTFs injected into the brain rescue and regenerate certain neuronal populations lost in neurodegenerative diseases, demonstrating the potential of NTFs to cure the diseases rather than simply alleviating the symptoms. NTFs (as the vast majority of molecules) do not pass through the blood–brain barrier (BBB) and therefore, are delivered directly into the brain of patients using costly and risky intracranial surgery. The delivery efficacy and poor diffusion of some NTFs inside the brain are considered the major problems behind their modest effects in clinical trials. Thus, there is a great need for NTFs to be delivered systemically thereby avoiding intracranial surgery. Nanoparticles (NPs), particles with the size dimensions of 1-100 nm, can be used to stabilize NTFs and facilitate their transport through the BBB. Several studies have shown that NTFs can be loaded into or attached onto NPs, administered systemically and transported to the brain. To improve the NP-mediated NTF delivery through the BBB, the surface of NPs can be functionalized with specific ligands such as transferrin, insulin, lactoferrin, apolipoproteins, antibodies or short peptides that will be recognized and internalized by the respective receptors on brain endothelial cells. In this review, we elaborate on the most suitable NTF delivery methods and envision “ideal” NTF for Parkinson’s disease (PD) and clinical trial thereof. We shortly summarize clinical trials of four NTFs, glial cell line-derived neurotrophic factor (GDNF), neurturin (NRTN), platelet-derived growth factor (PDGF-BB), and cerebral dopamine neurotrophic factor (CDNF), that were tested in PD patients, focusing mainly on GDNF and CDNF. We summarize current possibilities of NP-mediated delivery of NTFs to the brain and discuss whether NPs have impact in improving the properties of NTFs and delivery across the BBB. Emerging delivery approaches and future directions of NTF-based nanomedicine are also discussed. Neurotrophic factors (NTFs)  are typically proteins of 10 to 35 kDa in molecular weight that support the development, differentiation, survival and plasticity of neurons . NTF-bas(a)NTFs are disease-modifying. All commercial and most of the emerging therapeutic approaches alleviate the symptoms of neurodegenerative diseases without curing them, while NTFs are able to slow down neurodegeneration and reverse the diseases at least in certain animal models and in some clinical trials .(b)Decrease of NTF levels or knockdown of their receptors results in neuronal loss and other disease-related outcomes. Decreased levels of NTFs have been found in the brains of AD, HD, and PD patients , while s(c)NTFs regulate the functional activity of neurons. This is achieved by regeneration of neuronal axons, stabilization and stimulation of synapses and regulation of the synthesis and release of neurotransmitters and expression of their transporters .in vivo half-lives, poor pharmacokinetic properties and very low penetration rates through the blood–brain barrier (BBB). Thus, their access to the neuronal targets is restricted by their proteolytic degradation, different clearance mechanisms (such as rapid excretion by kidneys) and binding by various components of peripheral tissues -based strategies to improve the stability and delivery of NTFs into the brain. We focus mainly on the delivery of NTFs in PD, and cover well-known NTFs as well as a new family of unconventional NTFs consisting of mesencephalic astrocyte-derived neurotrophic factor (MANF) and cerebral dopamine neurotrophic factor (CDNF) that have recently shown considerable therapeutic potential in the animal models of PD.Parkinson’s disease is the second most common neurodegenerative disease that affects over 10 million people throughout the world. PD is characterized by progressive loss of nigrostriatal dopaminergic neurons in the midbrain that leads to severe movement disorders  and lossNerve growth factor (NGF) was the first NTF used in PD patients, and it was tested in one PD patient as support for the adrenal chromaffin tissue graft in the putamen . In the Glial cell line-derived neurotrophic factor is the most studied NTF in PD. GDNF acts on neurons through its receptor, tyrosine kinase rearranged during transfection (RET) in the presence of a co-receptor, GDNF Family Receptor α1 (GFRα1) . RET actSix clinical trials in PD patients with GDNF were conducted. Two open-label trials demonstrated the improvement in UPDRS , whereasEscherichia coli that rendered unglycosylated GDNF. GDNF has seven S-S-bridges that are not formed in E. coli. For these reasons bacterially produced GDNF was shown to possess a lower stability and activity than the GDNF produced in mammalian cells  patients in the GDNF-treated group but no placebo patients with a large clinically important motor improvement (≥10 points) in the OFF state. post hoc covariate analyses investigating phenotypic characteristics such as age, disease duration, disease severity, and tremor predominance did not identify any subtype of the patients who experienced an enhanced benefit  was shown to be lower compared to CDNF. While MANF demonstrated potential to rescue cell bodies of dopamine neurons in the substantia nigra (SN) pars compacta (SNpc) in a 6-OHDA rat model, its protective effect on neuronal axons (the fibers of dopamine neurons in the striatum) was modest or absent ;2.Good diffusion in the brain enabling to reach target cells;3.Stability in the body fluids  and tissues enabling to reach the target cells in sufficient concentrations;4.Specificity toward dopamine neurons enabling reduction of side effects;5.Ability to treat non-motor symptoms;6.Systemic delivery without side effects and immune response;7.Possibility of starting treatment soon after diagnosis when significant number of dopamine neurons are still alive.Systemic (non-invasive) administration of NTFs would be the ideal method of delivery. Although early research articles demonstrated some benefits of NTFs delivered systemically, later better controlled studies failed to replicate the efficiency or identified serious side effects of NTFs that limited the dosage . These dDegeneration of dopamine neurons starts from their synapses and the axons in caudate putamen , whereasThere are mainly two methods to deliver NTFs directly into the brain:(1)The intracerebroventricular method that relies on the implantation of a catheter and or an internal reservoir with the drug followed by controlled drug injection from this reservoir into lateral ventricle.(2)The intraparenchymal/intracerebral method relying on the placement of tiny catheters into the brain parenchyma and continuous or periodical connection of the catheters to the external drug reservoir. Drug either diffuses inside the brain by a concentration gradient (“regular” injection) or “pumped” using a positive pressure gradient pump [convection enhanced delivery (CED)] .In the first attempt to treat human PD patients with GDNF, the intracerebroventricular delivery method was applied and resulted in no improvement in the UPDRS . Since Gin vivo, There is still a debate regarding the NTF doses and continuity of infusion to achieve the best results. The majority of clinical trials in PD patients have been conducted using continuous infusion of high doses of NTFs or their constitutive overexpression from viral vectors. However, by characterizing the distribution, toxicity and the functional effects of GDNF after CED into the striatum of rats When PD is first diagnosed, there is around 50–70% reduction in the density of axons of dopamine neurons in the putamen and about 30% reduction in the number of cell bodies in the SNpc . By 5–6 via stereotactic surgery . In the current review we mean manufactured (synthetic) nanoparticles.Nanomedicine:“A branch of medicine that applies the knowledge and tools of nanotechnology to the prevention and treatment of disease. Nanomedicine involves the use of nanoscale materials /…/ for diagnosis, delivery, sensing or actuation purposes in a living organism” . Colloquially, the plural form “nanomedicines” usually refers to the products of nanomedicine.Within the realm of nanomedicine, NPs are often used as non-viral vectors for drug delivery to different cells and organs, including the brain. Depending on the properties of the drugs, they can be either placed into NPs or attached to their surfaces. The first NPs for drug delivery were developed in the 1960s . DespiteMost of the approved nanomedicines are anti-cancer drugs, whereas the main benefit of “nano” is in the improvement of the physico-chemical properties and stability of the active drug and its passive accumulation in tumor cells, while the active cell- and organ-targeting has not been achived yet, despite some encouraging data from animal models. In the highly cited and discussed article, after analyzing the scientific literature from the past 10 years, in vivo , poly(lactic-co-glycolic acid) (PLGA), poly(glycolic acid) (PGA), poly(L-glutamic acid) (PLE), poly(lactic acid) (PLA), human serum albumin, and chitosan. One of the first polymeric NPs for NTF delivery to the brain was PBCA NPs, which have been increasingly replaced by biodegradable PLA, PLE, or PLGA NPs. PLGA NPs have been approved by FDA and EMA for use in drug delivery systems .Dendrimers, such as polyamidoamine dendrimers (PAMAMs), have been successfully used for the delivery of NTF genes. Under physiological conditions, PAMAM-DNA complexes have a positive net charge that facilitates their interaction with net negatively charged cell membrane.per se prevented and reversed alpha-synuclein (αSyn) aggregation in a PD model [graphene quantum dots  and overcoated the construct with PX188 to enhance their brain targeting. We demonstrated that a 1.5-fold more radioactivity  was detected in the brain of rats in terms of the CDNF adsorbed to NPs (125I-CDNF-NP) compared to free non NP adsorbed CDNF (125I-CDNF) 1 h after subcutaneous injection. In addition to the radioactivity in the brain, we also measured radioactivity values in other organs as a proxy for CDNF distribution. We observed that: (1) the fraction of CDNF was negligible in the brain (0.03% without NPs and 0.046% with NPs) compared to other organs, and (2) in most organs, their radioactivity levels were increased in terms of CDNF-NP compared to free CDNF  that guide NPs to the brain . The preocytosis . In our ree CDNF . This suin vitro BBB model than transferrin and lactoferrin , or penetrate directly through cellular membranes (cell-penetrating peptides) . Some retoferrin , angiopetoferrin . Rotenonin vivo in mice after i.v. administration and subsequent ultrasound-assisted transient BBB opening. Both GDNF and BDNF provided a neuroprotective effect in a mouse MPTP model of PD, with improvements shown in behavioral deficits and rescued dopamine neurons  that oscillate during the application of ultrasound, leading to transient opening of the BBB. Recently, MBs-functionalized liposomes with GDNF or/and BDNF genes were successfully delivered through the BBB  neurons , 2020.An alternative non-invasive delivery method bypassing the BBB is intranasal delivery  that canAn interesting intranasal delivery system was recently proposed by One of the latest non-invasive delivery methods bypassing the BBB is a newly discovered methodology utilizing the brain lymphatic vasculature. Recent proof-of-concept study demonstrated that this method, which relies on subcutaneous injection of NPs at the neck near the lymph node, is 44-fold more efficient compared to conventional i.v. route for fluorescent-dye loaded PLGA NPs in mice . To the The NP-mediated delivery of NTFs to the brain is a complex phenomenon and its efficiency is a sum of several components: (a) stability of NTFs in the body fluids, (b) ability of NTFs to penetrate the BBB, and (c) diffusion of NTFs in the brain and their bioavailability to the target cells. Very few studies have so far addressed all of these components and mostly have reported the final result: improved locomotor behavior, reduced loss of TH+ neurons in the SN or the fold increase of NTF-NP concentration in the brain compared to the free NTFs. Below we elaborate on different components of successful NP-mediated delivery of NTFs to the brain and briefly summarize what may be achieved by the means of NPs.Clearly, NPs can improve the stability of NTFs in the body fluids. While free NTFs are easily removed from circulation due to their rapid degradation by extracellular peptidases, tissue binding, receptor-mediated clearance, and glomerular filtration , placeme125I-CDNF-NP in the brain of naive rats compared to free 125I-CDNF  NTFs is not significantly restricted, while larger NTFs (>40 kDa) whose sizes begin to resemble the dimensions of extracellular space (15–40 nm), may encounter diffusion restrictions . In addiin vivo and ex vivo in brain tissues that PEG-functionalized PLGA NPs diffuse in normal rat brain and PLGA NPs without PEG functionalization do not, whereas the percent of diffusive fractions correlated with the PEG surface density and NP size  that promote the survival of different neuronal populations. Despite their promising neurorestorative properties, these molecules still suffer from poor pharmacological characteristics, do not efficiently penetrate the BBB, and activate several receptors in different cell types . NPs couin vivo conversion of astrocytes into dopamine neurons that currently relies on genes of transcription factors that are delivered into the brain using lentiviruses injected into the striatum  stress caused by pathological processes in the brain of patients with neurodegenerative diseases. This emerging dual strategy that combines drug carrier and therapeutic function of NPs may be of significance.in vitro in the cell line SN4741 derived from the murine SN (via modulation of the NF-κB pathway (Several research articles reported improved growth, differentiation or survival of neuronal cells and neurons on nanomaterials, especially on carbon-based materials such as graphene , carbon urine SN . Graphenurine SN . Nanodia pathway . Similar pathway  and ceri pathway . Similar pathway . Thus, sin vivo in an αSyn fibrils-induced mouse model of PD: stereotaxically injected αSyn provoked accumulation of fibrils in the striatum and SN but systemic administration of graphene quantum dots reduced the levels of phosphorylated αSyn in murine brain and reduced behavioral deficits. The mechanism of pathological fibrillar remodeling is not fully understood but it is most probably attributed to the reduction of β-sheets and increase of α-helices and random coils in the secondary structure of αSyn fibrils by graphene quantum dots. Since quantum dots contained a high number of COOH groups on their surface, these groups could interact with the positively charged N-terminal domain of α-Syn and facilitate disaggregation of αSyn fibrils (via dual strategies combining the properties of NPs as drug carriers and as drugs themselves to mitigate protein aggregation and ER stress.Aggregation of proteins into pathological fibrils and subsequent ER stress caused by misfolded proteins are common hallmarks of a range of neurodegenerative diseases including Aβ in AD and αSyn in PD. Inhibiting protein amyloid aggregation has become one of the popular approaches to potentially treat AD and PD. Several articles have recently demonstrated that Au and carbon-based NPs efficiently penetrated the BBB and, in addition to their nanocarrier function, prevented and reversed αSyn aggregation in PD models and Aβ aggregation in AD models. It has been demonstrated that graphene quantum dots not only prevented formation of αSyn fibrils but also disassembled formed fibrils . Specifi fibrils . Similar fibrils , probabl fibrils . Javed eBoth authors planned and wrote the manuscript, and approved the final version of the manuscript.MS is the inventor in the MANF- and CDNF-related patents owned by Herantis Pharma Plc. OB is the shareholder in Herantis Pharma Plc.


Selecting patients with peritoneal metastases from colorectal cancer (CRCPM) who might benefit from cytoreductive surgery followed by hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) is challenging. Computed tomography generally underestimates the peritoneal tumor load. Diagnostic laparoscopy is often used to determine whether patients are amenable for surgery. Magnetic resonance imaging (MRI) has shown to be accurate in predicting completeness of CRS. The aim of this study is to determine whether MRI can effectively reduce the need for surgical staging.The study is designed as a multicenter randomized controlled trial (RCT) of colorectal cancer patients who are deemed eligible for CRS-HIPEC after conventional CT staging. Patients are randomly assigned to either MRI based staging (arm A) or to standard surgical staging with or without laparoscopy (arm B). In arm A, MRI assessment will determine whether patients are eligible for CRS-HIPEC. In borderline cases, an additional diagnostic laparoscopy is advised. The primary outcome is the number of unnecessary surgical procedures in both arms defined as: all surgeries in patients with definitely inoperable disease (PCI > 24) or explorative surgeries in patients with limited disease (PCI < 15). Secondary outcomes include correlations between surgical findings and MRI findings, cost-effectiveness, and quality of life (QOL) analysis.This randomized trial determines whether MRI can effectively replace surgical staging in patients with CRCPM considered for CRS-HIPEC.NCT04231175.Registered in the clinical trials registry of U.S. National Library of Medicine under  Peritoneal metastatic disease is the dissemination of cancer within the abdominal cavity. It is the second leading cause of death in patients with colorectal cancer (CRC). 10.6% of CRC patients present with peritoneal metastases at diagnosis or will develop peritoneal metastases at a later stage –4. MacroCT is the preferred first-line imaging tool for the detection of peritoneal metastases but falls short when used to assess the total peritoneal tumor burden –16. MagnThe primary objective of this study is to determine whether additional preoperative dedicated MRI staging to can reduce the number of futile (exploratory) surgeries in patients with CRC considered for CRS-HIPEC as compared to the standard of care of CT alone. An unnecessary surgical procedure is defined as any non-therapeutic laparotomy or diagnostic laparoscopy in patients, with exception of patients with borderline operable disease (15<PCI> 24).https://clinicaltrials.gov/ct2/show/NCT04231175). Patients suspected of having CRC peritoneal metastases and considered for CRS-HIPEC, are eligible for inclusion. Patients are randomly assigned to one of two diagnostic arms towards CRS-HIPEC. A trial flow diagram is presented in Fig. This investigator-initiated, multi-center, randomized controlled trial is performed in Dutch HIPEC centers since September 2019. The study is conducted according to the principles of the Declaration of Helsinki and in accordance with the Medical Research Involving Human Subjects Act (WMO) and was approved by the medical ethics committee at the Netherlands Cancer Institute  and is retrospectively registered in the clinical trials registry of U.S. National Library of Medicine under NCT04231175 (Patients with suspicion of CRCPM and considered for CRS-HIPEC after CT imagingAge ≥ 18 yearsWritten and signed informed consentPerformance status of WHO 0–2Able and willing to drink 1 l of pineapple or blueberry juice (required as a preparatory step for the dedicated MRI)In order to be eligible to participate in this study, a subject must meet all of the following criteria:Patients with contraindications for MRIPatients with clinical contraindications for CRS-HIPEC, such as but not limited to inadequate organ or hematological function, significant medical history, active pregnancy and lactation, or old agePatients with radiological contra-indications for CRS-HIPEC observed on CT thorax/abdomenPatients with concurrent or history of other malignancy within ≤5 years prior to CRCPM diagnosisA potential subject who meets any of the following criteria will be excluded from participation in this study:Eligible patients are identified and informed about the study by their treating physician at the participating center. Patients are included after written informed consent. Patients are randomly assigned to an experimental arm (A) or a control arm (B). The random assignment is performed by dedicated medical data managers or a research nurse using specific clinical trial management software . A random block randomization is used and stratified per participating center. Blinding is not possible with this trial set-up.○ Peritoneal cancer index estimated on MRI (MRI-PCI) < 15 and no non-peritoneal lesions (that contra-indicate CRS-HIPEC)CRS-HIPEC is feasible; perform CRS-HIPEC○ MRI-PCI between 15 and 24 and no non-peritoneal lesions (that contra-indicate CRS-HIPEC)CRS-HIPEC might be feasible; consider diagnostic laparoscopy (DLS) to determine whether CRS-HIPEC is feasible and justifiable○ MRI-PCI > 24 and/or detection of non-peritoneal lesions (that contra-indicate CRS-HIPEC)CRS-HIPEC is not feasible; chemotherapy or best supportive carePatients in Arm A receive a dedicated 3 T MRI scan, which includes T2 weighted, T1 weighted, diffusion weighted and non-enhanced + gadolinium enhanced fat-suppressed T1 weighted imaging of the pelvis and abdomen (and thorax on DWI), as previously described . PatientIn the Netherlands, patients are eligible for CRS-HIPEC if the PCI does not exceed 20 at surgical exploration . All parIn arm B, patients undergo the standard diagnostic work-up followed by a DLS at the discretion of the MDT, as determined before randomization. For the control group no study specific guidelines for DLS use have been determined, centers are expected to continue implementing DLS according to their own current policies. The rate of laparoscopy use may therefore vary between centers.All patients will be asked to fill in two QOL questionnaires (EORTC-C30 and EQ5D5L) at baseline (randomization), at 3 months, and 6 months. At 6 months after CRS-HIPEC, all patients undergo a follow-up of CT, MRI, serum biomarkers , and physical examination to screen for early disease recurrence in the peritoneum, liver, or elsewhere. This will also serve as an extra quality check of diagnostic and surgical outcome. It is expected that a residual peritoneal or non-peritoneal metastasis will have become apparent at 6 months on MRI. If residual disease of early recurrence is observed, treatment is at the discretion of the local MDT. The trial schedule is summarized in Table All study MRIs will be evaluated by an abdominal radiologist with experience in DWI of the participating center and by experienced abdominal radiologists of the trial-initiating center with extensive experience with the study protocol dedicated to peritoneal metastasis evaluation, independently. The findings of the radiologists then will be shared and discussed before the MDT meeting. In case of discrepant findings, the findings from the trial-initiating center’s radiologist are leading. Radiologists of the participating centers will undergo training in the study specific MRI evaluations, followed by on-the-job training with continued feedback of the trial-initiating center.Criteria used to establish the presence of peritoneal disease on MRI include the presence of high signal on DWI with a corresponding soft tissue lesion of peritoneal thickening on T2 weighted or contrast enhanced T1 weighted images, as previously described .Basic clinical information is collected, including patient history, primary tumor location, tumor histology, previous surgical procedures, chemotherapy and/or radiotherapy history, and serum biomarkers. For each abdominal assessment preformed to assess eligibility for CRS-HIPEC , a case report form (CRF) is filled out including the same parameters for each assessment, where appropriate. These parameters include the PCI, the presence of organ infiltration, the presence and pattern of miliary spread, presence of non-PM (such as liver and lymph node metastases) and diaphragmatic involvement. Parameters specific to radiological assessments  include scan quality, scan completion, presence of extra abdominal metastases , and presence of pleural effusion. For each radiological finding, the reader will indicate whether the feature is present (yes/no) and how certain he or she is of that decision (not certain/ quite certain/ certain). Parameters specific to surgical assessment include extent of adhesiolysis and accessibility. Surgical findings are considered the reference standard. No confidence level will be applied to those parameters. For the laparotomies that proceed to CRS-HIPEC, a separate CRF registers which resections, excisions, and/or extirpations have been performed, as well as the completeness of cytoreduction (resection status). All data is collected by the local research team, consisting of at least one radiologist, one surgeon, and a research nurse and/or medical data manager. The pseudo-anonymized data is entered and stored with the same clinical trial management software used for randomization  in an ISO 27001 certified hosting facility in the Netherlands.The primary outcome measure is a composite endpoint of futile surgical explorations. A futile surgical exploration is defined as: all surgeries in patients with definitely inoperable disease (PCI > 24) or explorative surgeries in patients with limited disease (PCI < 15).number of incomplete CRS-HIPECs (R2a/ R2b/ open-close),number of residual disease events or early recurrences at 6 months after a complete resection at CRS-HIPEC,number of non-peritoneal metastases,diagnostic performance of MRI and diagnostic laparoscopy to predict whether complete CRS-HIPEC is feasible,correlations between MRI findings and surgical findings,incremental cost-effectiveness,Patient reported QOL between study arms.The secondary outcomes include:Direct medical costs include both the immediate medical costs such as diagnostic tests and initial treatments (including side-effects), as well as later treatments. Direct costs incorporated in the current study include costs of standard diagnostic staging (CT+/−laparoscopy), CRS-HIPEC and treatment of recurrences, follow-up visits and palliative care. Resource use data will be collected from the hospital’s administrative database. Where appropriate, Dutch guidelines for costing studies will be used in applying tariffs to units of resource use .For the health related quality of life (QoL), the EORTC-C30 questionnaire will be used . For cosPower calculations are based on an expected reduction of futile surgical explorations from 30 to 15% by MRI staging. With a two-sample two-sided test of binomial proportions and an α of 0.05, a ß of 0.20, and an expected drop-out rate of 20%, 272 patients are to be included in total.The observed difference in preventable surgical explorations between trial arms will be tested with a McNemar’s chi-squared test, as well as the difference in incomplete CRS-HIPECs, non-peritoneal findings before surgery, and early recurrences or residual disease visible at first follow-up (6 months). Progression free survival will be analyzed by binomial logical regression analysis. Progression free survival is defined as the time in days from complete CRS-HIPEC to recurrence or progression of disease as determined by the multidisciplinary team meeting or death of any cause. Correlations between MRI staging and surgical staging will be evaluated by intraclass correlation coefficients (ICC), Cohen’s kappa, and Cohen’s weighted kappa, where appropriate. Diagnostic performance of MRI and surgical staging to predict complete CRS will be compared by confusion matrix analysis and receiver operator characteristic analysis. Differences in predictive values will be tested with McNemar’s test and the DeLong test, where appropriate.A cost-effectiveness Analysis will be performed with incremental costs per Quality Adjusted Life Year gained as outcome for patients with PM undergoing MRI versus usual diagnostic work-up for selection for CRS-HIPEC. A Markov model will be constructed, a lifelong time horizon with 3 months cycle length will be used, and a societal perspective from the Netherlands will be adopted. Future costs and effects will be discounted to their present value by a rate of 4 and 1.5% per year respectively, according to Dutch guidelines . The resSelected CRC patients with limited PM can benefit from CRS-HIPEC with a chance of a significantly prolonged survival and in some cases even cure. Currently, the final clinical decision of whether complete resection at CRS-HIPEC is feasible is often determined during surgery. Rehabilitation from open-close surgery is not in the best interest of a palliative patient and may delay palliative treatment or inclusion in trials. Two trials are ongoing in the Netherlands exploring novel palliative strategies for patients with extensive CRCPM, namely the use of concomitant intraperitoneal and systemic chemotherapy (INTERACT) and repetitive electrostatic pressurized intraperitoneal aerosol chemotherapy with oxaliplatin (ePIPAC) , 28.Twenty-three percent of candidates for the PRODIGE-7 trial were excluded at laparotomy due to the extent of PM, liver metastases or non-resectable disease . Other sA limitation of MRI in the work up of CRC patients with PM is the lack of histopathological proof of identified lesions. However, we expect that in most cases patients will have lesions that are accessible by biopsy or present with proven PM during a previous surgical procedure. If this is not the case, a DLS may still be necessary. Patients with severe claustrophobia as well as patients with metal implants non-compatible with MRI are not eligible for MRI assessment. Policy differences between hospitals may lead to differences in laparoscopy rates and open-close rates in the control arm. Assuming that the rate of DLS is inversely related to the incomplete and open-close rate, the potential benefit of additional MRI staging could nonetheless become apparent. Furthermore, the benefit of Oxaliplatin-based HIPEC in the combined CRS-HIPEC procedure has recently come under debate following the results of the PRODIGE-7 trial . HoweverIf MRI staging effectively reduces the number of surgical explorations in CRS-HIPEC candidates, patients with PM from CRC will be exposed to a less invasive and more effective triaging system.