Recent Clinical Implications of FAPI: Imaging and Therapy.

ABSTRACT: The fibroblast activation protein (FAP) is a biomarker that is selectively overexpressed on cancer-associated fibroblasts (CAFs) in various types of tumoral tissues and some nonmalignant diseases, including fibrosis, arthritis, cardiovascular, and metabolic diseases. FAP plays a critical role in tumor microenvironment through facilitating proliferation, invasion, angiogenesis, immunosuppression, and drug resistance. Recent studies reveal that FAP might be regarded as a promising target for cancer diagnosis and treatment. FAP-targeted imaging modalities, especially PET, have shown high sensitivity and specificity in detecting FAP-expressing tumors. FAP-targeted imaging can potentially enhance tumor detection, staging, and monitoring of treatment response, and facilitate the development of personalized treatment strategies. This study provides a comprehensive view of FAP and its function in the pathophysiology of cancer and nonmalignant diseases. It also will discuss the characteristics of radiolabeled FAP inhibitors, particularly those based on small molecules, their recent clinical implications in imaging and therapy, and the associated clinical challenges with them. In addition, we present the results of imaging and biodistribution radiotracer 68Ga-FAPI-46 in patients with nonmalignant diseases, including interstitial lung disease, primary biliary cirrhosis, and myocardial infarction, who were referred to our department. Our results show that cardiac FAP-targeted imaging can provide a novel potential biomarker for managing left ventricle remodeling. Moreover, this study has been organized and presented in a manner that offers a comprehensive overview of the current status and prospects of FAPI inhibitors in the diagnosis and treatment of diseases.

An in-silico study on the mechanical behavior of colorectal cancer cell lines in the micropipette aspiration process.

Cancer alters the structural integrity and morphology of cells. Consequently, the cell function is overshadowed. In this study, the micropipette aspiration process is computationally modeled to predict the mechanical behavior of the colorectal cancer cells. The intended cancer cells are modeled as an incompressible Neo-Hookean visco-hyperelastic material. Also, the micropipette is assumed to be rigid with no deformation. The proposed model is validated with an in-vitro study. To capture the equilibrium and time-dependent behaviors of cells, ramp, and creep tests are respectively performed using the finite element method. Through the simulations, the effects of the micropipette geometry and the aspiration pressure on the colorectal cancer cell lines are investigated. Our findings indicate that, as the inner radius of the micropipette increases, despite the increase in deformation rate and aspirated length, the time to reach the equilibrium state increases. Nevertheless, it is obvious that increasing the tip curvature radius has a small effect on the change of the aspirated length. But, due to the decrease in the stress concentration, it drastically reduces the equilibrium time and increases the deformation rate significantly. Interestingly, our results demonstrate that increasing the aspiration pressure somehow causes the cell stiffening, thereby reducing the upward trend of deformation rate, equilibrium time, and aspirated length. Our findings provide valuable insights for researchers in cell therapy and cancer treatment and can aid in developing more precise microfluidic.

How living cells are affected during the cold atmospheric pressure plasma treatment.

When the electric discharge process is limited by high voltage electrodes shielding, the ionization measure would be controlled to less than one percent and the temperature to less than 37 °C even at atmospheric pressure, so-called cold atmospheric pressure plasma (CAP). CAP has been found to have profound medical applications in association with its reactive oxygen and nitrogen species (ROS/RNS). In this way that during plasma exposure, the subjected medium (e.g. cell cytoplasmic membrane in plasma therapy) interacts with ROS/RNS. Accordingly, a precise study of the mentioned interactions and their consequences on the cells' behavior changes, is necessary. The results lead to the reduction of possible risks and provide the opportunity of optimizing the efficacy of CAP before the development of CAP applications in the field of plasma medicine. In this report molecular dynamic (MD) simulation is used to investigate the mentioned interactions and a proper and compatible comparison with the experimental results is presented. Based on this, the effects of H2O2, NO and O2 on the living cell's membrane are investigated in biological conditions. Our results show that: i) The hydration of phospholipid polar heads would be enhanced associated with the H2O2 presence. ii) A new definition of the surface area assigned to each phospholipid (APL), more reliable and compatible with the physical expectations, is introduced. iii) The long-term behavior of NO and O2 is their penetration into the lipid bilayer and sometimes passing through the membrane into the cell. The latter would be an indication of internal cells' pathways activation leading to modification of cells' function.

DNA sequencing via molecular dynamics simulation with functionalized graphene nanopore.

Through this research, functionalized graphene nanopores are used to verify how effective such an apparatus for DNA sequencing is. The circular symmetric pores are functionalized with hydrogen and a hydroxyl group bonded with carbon atoms of the pore rim. Plus, two adenine bases are also put at the rim perimeter to verify whether such a combination would lead to base detection. A homopolymer of single-stranded DNA (ssDNA) is pulled through a nanopore using steered molecular dynamics (SMD) simulation. Pulling force profile, moving fashion of ssDNA in irreversible DNA pulling as well as the base orientation during translocation relative to the graphene plane, called beta angle, are assessed. Based on the studied parameters, SMD force, and base orientation, the hydrogenated and hydroxylated pores do not show a clear distinction between bases, while the adenine-functionalized pore can distinguish between adenine and cytosine. Therefore, there may be some hope for achieving single-base sequencing, while further research is needed.

Probing the mechanical properties of ORF3a protein, a transmembrane channel of SARS-CoV-2 virus: Molecular dynamics study.

SARS-CoV-2-encoded accessory protein ORF3a was found to be a conserved coronavirus protein that shows crucial roles in apoptosis in cells as well as in virus release and replications. To complete the knowledge and identify the unknown of this protein, further comprehensive research is needed to clarify the leading role of ORF3a in the functioning of the coronavirus. One of the efficient approaches to determining the functionality of this protein is to investigate the mechanical properties and study its structural dynamics in the presence of physical stimuli. Herein, performing all-atom steered molecular dynamics (SMD) simulations, the mechanical properties of the force-bearing components of the ORF3a channel are calculated in different physiological conditions. As variations occurring in ORF3a may lead to alteration in protein structure and function, the G49V mutation was also simulated to clarify the relationship between the mechanical properties and chemical stability of the protein by comparing the behavior of the wild-type and mutant Orf3a. From a physiological conditions point of view, it was observed that in the solvated system, the presence of water molecules reduces Young's modulus of TM1 by ∼30 %. Our results also show that by substitution of Gly49 with valine, Young's modulus of the whole helix increases from 1.61 ± 0.20 to 2.08 ± 0.15 GPa, which is consistent with the calculated difference in free energy of wild-type and mutant helices. In addition to finding a way to fight against Covid-19 disease, understanding the mechanical behavior of these biological nanochannels can lead to the development of the potential applications of the ORF3a protein channel, such as tunable nanovalves in smart drug delivery systems, nanofilters in the new generation of desalination systems, and promising applications in DNA sequencing.

Asymmetric effects of amphipathic molecules on mechanosensitive channels.

Mechanosensitive (MS) ion channels are primary transducers of mechanical force into electrical and/or chemical intracellular signals. Many diverse MS channel families have been shown to respond to membrane forces. As a result of this intimate relationship with the membrane and proximal lipids, amphipathic compounds exert significant effects on the gating of MS channels. Here, we performed all-atom molecular dynamics (MD) simulations and employed patch-clamp recording to investigate the effect of two amphipaths, Fluorouracil (5-FU) a chemotherapy agent, and the anaesthetic trifluoroethanol (TFE) on structurally distinct mechanosensitive channels. We show that these amphipaths have a profound effect on the bilayer order parameter as well as transbilayer pressure profile. We used bacterial mechanosensitive channels (MscL/MscS) and a eukaryotic mechanosensitive channel (TREK-1) as force-from-lipids reporters and showed that these amphipaths have differential effects on these channels depending on the amphipaths' size and shape as well as which leaflet of the bilayer they incorporate into. 5-FU is more asymmetric in shape and size than TFE and does not penetrate as deep within the bilayer as TFE. Thereby, 5-FU has a more profound effect on the bilayer and channel activity than TFE at much lower concentrations. We postulate that asymmetric effects of amphipathic molecules on mechanosensitive membrane proteins through the bilayer represents a general regulatory mechanism for these proteins.

Metamorphosis of prostate specific membrane antigen (PSMA) inhibitors.

Prostate-specific membrane antigen (PSMA), also called glutamate carboxypeptidase II (GCP(II)), is a Zn-dependent metalloprotease that is known as a well prostate cancer indication and a potential targeting towards anti-cancer medicines and drug delivery. Because of its centrality in the diagnostics and treatment of prostate cancer, several types of inhibitors are designed with particular scaffolds. In this study, important groups of related inhibitors as well as reported experimental and computational studies are being reviewed, in which we examined three functional groups on each group of structures. The importance of computational biochemistry and the necessity of extensive research in this area on PSMA and its effective ligands are recommended.

Gold-based hybrid nanostructures: more than just a pretty face for combinational cancer therapy.

The early diagnosis together with an efficient therapy of cancer is essential to treat cancer patients and to enhance their quality of life. The use of nanostructures, as a newer technology, has demonstrated proven benefits as efficient cancer theranostic agents in numerous recent studies. Having a tunable surface plasmon resonance, gold nanostructures have been the subject of many recent studies as excellent imaging and photothermal therapy agents. However, the potential cytotoxicity and weak stability of gold nanostructures necessitate further modifications using biocompatible materials for biological applications. Based on the composition of the final structure, these gold-based hybrid nanostructures (GHNs) could be divided into five major groups; each of which has specific pros and cons. Understanding the strengths and weaknesses of each group helps scientists to optimize GHN designs with multiple functions by synergizing the benefits of different groups. This review aims to summarize the advancements in GHN design and provide a perspective view of future requirements for successful GHN-based targeted combinational cancer theranostic platforms.

DNA sequencing: an overview of solid-state and biological nanopore-based methods.

The field of sequencing is a topic of significant interest since its emergence and has become increasingly important over time. Impressive achievements have been obtained in this field, especially in relations to DNA and RNA sequencing. Since the first achievements by Sanger and colleagues in the 1950s, many sequencing techniques have been developed, while others have disappeared. DNA sequencing has undergone three generations of major evolution. Each generation has its own specifications that are mentioned briefly. Among these generations, nanopore sequencing has its own exciting characteristics that have been given more attention here. Among pioneer technologies being used by the third-generation techniques, nanopores, either biological or solid-state, have been experimentally or theoretically extensively studied. All sequencing technologies have their own advantages and disadvantages, so nanopores are not free from this general rule. It is also generally pointed out what research has been done to overcome the obstacles. In this review, biological and solid-state nanopores are elaborated on, and applications of them are also discussed briefly.

Mechanical properties of ester- and ether-DPhPC bilayers: A molecular dynamics study.

In addition to its biological importance, DPhPC lipid bilayers are widely used in droplet bilayers, study of integral membrane proteins, drug delivery systems as well as patch-clamp electrophysiology of ion channels, yet their mechanical properties are not fully measured. Herein, we examined the effect of the ether linkage on the mechanical properties of ester- and ether-DPhPC lipid bilayers using all-atom molecular dynamics simulation. The values of area per lipid, thickness, intrinsic lateral pressure profile, order parameter, and elasticity moduli were estimated using various computational frameworks and were compared with available experimental values. Overall, a good agreement was observed between the two. The global properties of the two lipid bilayers are vastly different, with ether bilayer being stiffer, less ordered, and thicker than ester bilayer. Moreover, ether linkage decreased the area per lipid in the ether lipid bilayer. Our computational framework and output demonstrate how ether modification changes the mechano-chemical properties of DPhPC bilayers.

Possibility of making aerophobic surfaces by nanoprotrusions: an investigation of atomic-scale friction of the air-solid interfaces.

Emerging, new atomic-scale fabrication methods have enabled scientists to design and manufacture nanostructured devices for the investigation and application of nanoscale regimes in fluid mechanics. One of the most significant goals in designing these devices is finding an efficient way to reduce the friction of the fluid flow in/on the nanochannels and surfaces. Herein, a set of surfaces with various engineered nanoscale roughnesses (nanoprotrusions) was designed. In addition, a triple point charge/mass model of air molecules was developed based on realistic physicochemical characteristics. All-atom, non-equilibrium molecular dynamics simulations were employed to evaluate the atomic interaction of airflow/solid surfaces for various conditions, such as different fluid velocity, surface material, and geometry of nanoscale roughness. Our results show that there is a significant difference (more than six times) between the fluid/surface interaction energy for graphene and silicone surfaces. However, the interaction energy of the fluid/solid interface does not vary for atomic-scale roughnesses (<10 nm). Our results indicate that for solid surfaces coated by few-layer graphene in high Reynolds (supersonic) regimes, the outer graphene layers are confronted with delamination due to the high shear stress of airflow, which is a serious problem for the structure's strength and durability. We suggest that our computational findings shed light on designing aerophobic surface coatings in a wide range of applications, from nanodevices to conventional aircraft.

Potential effective inhibitory compounds against Prostate Specific Membrane Antigen (PSMA): A molecular docking and molecular dynamics study.

One of the most prevalent cancers in men is prostate cancer and could be managed with immunotoxins or antibody treatment. Because of the substantial rise of the Prostate-Specific Antigen and the Prostate-Specific Membrane Antigen (PSMA), cancer vaccination should be rendered with these antigens. Through pharmacodynamic experiments in a library of natural compounds from ZINC database, the current research sought to identify compounds that could suppress PSMA protein. To test the most productive compounds for further research, the Library has been scanned with Pharmacophore and ADMET analysis followed by molecular docking methods in the first phase. After selecting 15 ligands with the best pose related to docking results, to evaluate the stability of the ligand-protein bounds of the compounds, a molecular dynamics simulation considering the effect of the presence of zinc ions on the protein structure was performed. The measurement of ligand binding modes and free energy has shown that four compounds, including Z10, Z06, Z01, and Z03, have formed critical interactions with the active site's residues. Besides, multiple approaches were employed to determine their inhibition rating and describe the variables that facilitate the attachment of ligands to the protein active site. The results are obtained from the MMPBSA/GBSA analysis of four selected small molecules (Z10, Z06, Z01, and Z03), which are very close to the IC50 value of reference ligand (DCIBzl); they are -13.85 kcal/mol, -12.58 kcal/mol, -10.71 kcal/mol and -9.39 kcal/mol respectively. Finally, we evaluate the results obtained from selected ligands using hydrogen bond and decomposition analyzes. We have examined the effective interactions between ligands and S1/S1'pockets in protein. Our computational results illustrate the design of more efficient inhibitors of PSMA.

Dynamics of respiratory droplets carrying SARS-CoV-2 virus in closed atmosphere.

From the epidemiological point of view, the lifetime of cough and sneeze droplets in the ambient atmosphere plays a significant role in the transmission rate of Coronavirus. The lifetime of indoor respiratory droplets, per se, is a function of droplet size, ambient temperature, and humidity. In the attempt to explore the effective factors of droplet lifetime, sufficient knowledge of atomic-scale interactions and dynamics of the droplet with themselves, as well as the airflow molecules in the room space, is necessary. In this study, the vertical traveling of a wide range (100 nm-10 µm) of representative carrier droplets is studied in three ambient temperatures of 258, 298, and 318 K using all-atom molecular dynamics simulation. Our obtained results confirm that by increasing the room temperature, the suspending time of aerosol (suspended droplets carrying virus particles) increases due to the higher dynamics of air and evaporated water molecules in room space. In fact, by increasing the indoor temperature, the collision rate of aerosol and ambient atmosphere molecules increases significantly. Our result shows this higher rate of collision could have a dual effect on the lifetime of aerosol considering the fact of faster deposition of larger (heavier) droplet due to the gravitational force. On one hand, in higher temperatures, the higher collision can split the droplets to smaller ones with a semi-permanent suspension period. On the other hand, the higher dynamics of ambient molecules can lead to meet and coalesce of smaller cough/sneeze droplets making larger (heavier) droplets with faster sediment times. So, the role of indoor humidity to fuel the probability of coalescence phenomenon and lifetime of droplets becomes more determinant in the warmer spaces.

Design of peptide-based inhibitor agent against amyloid-ß aggregation: Molecular docking, synthesis and in vitro evaluation.

Formation of the amyloid beta (Aß) peptide aggregations represents an indispensable role in appearing and progression of Alzheimer disease. ß-sheet breaker peptides can be designed and modified with different amino acids in order to improve biological properties and binding affinity to the amyloid beta peptide. In the present study, three peptide sequences were designed based on the hopeful results of LIAIMA peptide and molecular docking studies were carried out onto the monomer and fibril structure of amyloid beta peptide using AutoDock Vina software. According to the obtained interactions and binding energy from docking, the best-designed peptide (d-GABA-FPLIAIMA) was chosen and synthesized in great yield (%96) via the Fmoc solid-phase peptide synthesis. The synthesis and purity of the resulting peptide were estimated and evaluated by Mass spectroscopy and Reversed-phase high-performance liquid chromatography (RP-HPLC) methods, respectively. Stability studies in plasma and Thioflavin T (ThT) assay were performed in order to measure the binding affinity and in vitro aggregation inhibition of Aß peptide. The d-GABA-FPLIAIMA peptide showed good binding energy and affinity to Aß fibrils, high stability (more than 90%) in human serum, and a reduction of 20% in inhibition of the Aß aggregation growth. Finally, the favorable characteristics of our newly designed peptide make it a promising candidate ß-sheet breaker agent for further in vivo studies.

A novel in silico platform for a fully automatic personalized brain tumor growth.

Glioblastoma Multiforme is the most common and most aggressive type of brain tumors. Although accurate prediction of Glioblastoma borders and shape is absolutely essential for neurosurgeons, there are not many in silico platforms that can make such predictions. In the current study, an automatic patient-specific simulation of Glioblastoma growth would be described. A finite element approach is used to analyze the magnetic resonance images from patients in the early stages of their tumors. For segmentation of the tumor, the Support Vector Machine (SVM) method, which is an automatic segmentation algorithm, is used. Using in situ and in vivo data, the main parameters of tumor prediction and growth are estimated with high precision in proliferation-invasion partial differential equation, using the genetic algorithm optimization method. The results show that for a C57BL mouse, the differences between the area and perimeter of in vivo test and simulation prediction data, as the objective function, are 3.7% and 17.4%, respectively.

Cell membrane mechanics and mechanosensory transduction.

The rapid progress in mechanobiology has brought together many scientific and engineering disciplines to work hand in hand toward better understanding of the role that mechanical force plays in functioning and evolution of different forms of life. New tools designed by engineers helped to develop new methods and techniques for investigation of mechanical properties of biological cells and tissues. This multidisciplinary approach made it clear that cell mechanics is tightly linked to intracellular signaling pathways, which directly regulate gene expression in response to mechanical stimuli originating outside or inside the cells. Mechanical stimuli act on mechanoreceptors which convert these stimuli into intracellular signals. In this chapter, we review the current knowledge about cell mechanics and the role cell mechanics plays for the function of mechanosensitive ion channels as a special class of mechanoreceptors functioning as molecular transducers of mechanical stimuli on a millisecond timescale.

Recent advances in the design and applications of amyloid-ß peptide aggregation inhibitors for Alzheimer's disease therapy.

Alzheimer's disease (AD) is an irreversible neurological disorder that progresses gradually and can cause severe cognitive and behavioral impairments. This disease is currently considered a social and economic incurable issue due to its complicated and multifactorial characteristics. Despite decades of extensive research, we still lack definitive AD diagnostic and effective therapeutic tools. Consequently, one of the most challenging subjects in modern medicine is the need for the development of new strategies for the treatment of AD. A large body of evidence indicates that amyloid-ß (Aß) peptide fibrillation plays a key role in the onset and progression of AD. Recent studies have reported that amyloid hypothesis-based treatments can be developed as a new approach to overcome the limitations and challenges associated with conventional AD therapeutics. In this review, we will provide a comprehensive view of the challenges in AD therapy and pathophysiology. We also discuss currently known compounds that can inhibit amyloid-ß (Aß) aggregation and their potential role in advancing current AD treatments. We have specifically focused on Aß aggregation inhibitors including metal chelators, nanostructures, organic molecules, peptides (or peptide mimics), and antibodies. To date, these molecules have been the subject of numerous in vitro and in vivo assays as well as molecular dynamics simulations to explore their mechanism of action and the fundamental structural groups involved in Aß aggregation. Ultimately, the aim of these studies (and current review) is to achieve a rational design for effective therapeutic agents for AD treatment and diagnostics.

Inorganic nanomaterials for chemo/photothermal therapy: a promising horizon on effective cancer treatment.

During the last few decades, nanotechnology has established many essential applications in the biomedical field and in particular for cancer therapy. Not only can nanodelivery systems address the shortcomings of conventional chemotherapy such as limited stability, non-specific biodistribution and targeting, poor water solubility, low therapeutic indices, and severe toxic side effects, but some of them can also provide simultaneous combination of therapies and diagnostics. Among the various therapies, the combination of chemo- and photothermal therapy (CT-PTT) has demonstrated synergistic therapeutic efficacies with minimal side effects in several preclinical studies. In this regard, inorganic nanostructures have been of special interest for CT-PTT, owing to their high thermal conversion efficiency, application in bio-imaging, versatility, and ease of synthesis and surface modification. In addition to being used as the first type of CT-PTT agents, they also include the most novel CT-PTT systems as the potentials of new inorganic nanomaterials are being more and more discovered. Considering the variety of inorganic nanostructures introduced for CT-PTT applications, enormous effort is needed to perform translational research on the most promising nanomaterials and to comprehensively evaluate the potentials of newly introduced ones in preclinical studies. This review provides an overview of most novel strategies used to employ inorganic nanostructures for cancer CT-PTT as well as cancer imaging and discusses current challenges and future perspectives in this area.

Tuning ion channel mechanosensitivity by asymmetry of the transbilayer pressure profile.

Mechanical stimuli acting on the cellular membrane are linked to intracellular signaling events and downstream effectors via different mechanoreceptors. Mechanosensitive (MS) ion channels are the fastest known primary mechano-electrical transducers, which convert mechanical stimuli into meaningful intracellular signals on a submillisecond time scale. Much of our understanding of the biophysical principles that underlie and regulate conversion of mechanical force into conformational changes in MS channels comes from studies based on MS channel reconstitution into lipid bilayers. The bilayer reconstitution methods have enabled researchers to investigate the structure-function relationship in MS channels and probe their specific interactions with their membrane lipid environment. This brief review focuses on close interactions between MS channels and the lipid bilayer and emphasizes the central role that the transbilayer pressure profile plays in mechanosensitivity and gating of these fascinating membrane proteins.

Structural Dynamics of the MscL C-terminal Domain.

The large conductance mechanosensitive channel (MscL), acts as an osmoprotective emergency valve in bacteria by opening a large, water-filled pore in response to changes in membrane tension. In its closed configuration, the last 36 residues at the C-terminus form a bundle of five α-helices co-linear with the five-fold axis of symmetry. Here, we examined the structural dynamics of the C-terminus of EcMscL using site-directed spin labelling electron paramagnetic resonance (SDSL EPR) spectroscopy. These experiments were complemented with computational modelling including molecular dynamics (MD) simulations and finite element (FE) modelling. Our results show that under physiological conditions, the C-terminus is indeed an α-helical bundle, located near the five-fold symmetry axis of the molecule. Both experiments and computational modelling demonstrate that only the top part of the C-terminal domain (from the residue A110 to E118) dissociates during the channel gating, while the rest of the C-terminus stays assembled. This result is consistent with the view that the C-terminus functions as a molecular sieve and stabilizer of the oligomeric MscL structure as previously suggested.