Image-based predictive modelling frameworks for personalised drug delivery in cancer therapy.

Personalised drug delivery enables a tailored treatment plan for each patient compared to conventional drug delivery, where a generic strategy is commonly employed. It can not only achieve precise treatment to improve effectiveness but also reduce the risk of adverse effects to improve patients' quality of life. Drug delivery involves multiple interconnected physiological and physicochemical processes, which span a wide range of time and length scales. How to consider the impact of individual differences on these processes becomes critical. Multiphysics models are an open system that allows well-controlled studies on the individual and combined effects of influencing factors on drug delivery outcomes while accommodating the patient-specific in vivo environment, which is not economically feasible through experimental means. Extensive modelling frameworks have been developed to reveal the underlying mechanisms of drug delivery and optimise effective delivery plans. This review provides an overview of currently available models, their integration with advanced medical imaging modalities, and code packages for personalised drug delivery. The potential to incorporate new technologies (i.e., machine learning) in this field is also addressed for development.

First Description of Novel End-Organ Effects by Speed Modulation Using the Aortix™ Device.

Aortix™ is a novel percutaneous mechanical circulatory support device designed to facilitate diuresis in patients with cardiorenal syndrome. We describe for the first time the development of end-organ hypoperfusion from excess blood acceleration at the nominal setting and demonstrate through temporal-perfusion marker curves, the potential for speed modulation to optimize results. This will inform future device development and investigation of patient-specific device titration.

Radiopharmaceutical transport in solid tumors via a 3-dimensional image-based spatiotemporal model.

Lutetium-177 prostate-specific membrane antigen (177Lu-PSMA)-targeted radiopharmaceutical therapy is a clinically approved treatment for patients with metastatic castration-resistant prostate cancer (mCRPC). Even though common practice reluctantly follows "one size fits all" approach, medical community believes there is significant room for deeper understanding and personalization of radiopharmaceutical therapies. To pursue this aim, we present a 3-dimensional spatiotemporal radiopharmaceutical delivery model based on clinical imaging data to simulate pharmacokinetic of 177Lu-PSMA within the prostate tumors. The model includes interstitial flow, radiopharmaceutical transport in tissues, receptor cycles, association/dissociation with ligands, synthesis of PSMA receptors, receptor recycling, internalization of radiopharmaceuticals, and degradation of receptors and drugs. The model was studied for a range of values for injection amount (100-1000 nmol), receptor density (10-500 nmol•l-1), and recycling rate of receptors (10-4 to 10-1 min-1). Furthermore, injection type, different convection-diffusion-reaction mechanisms, characteristic time scales, and length scales are discussed. The study found that increasing receptor density, ligand amount, and labeled ligands improved radiopharmaceutical uptake in the tumor. A high receptor recycling rate (0.1 min-1) increased radiopharmaceutical concentration by promoting repeated binding to tumor cell receptors. Continuous infusion results in higher radiopharmaceutical concentrations within tumors compared to bolus administration. These insights are crucial for advancing targeted therapy for prostate cancer by understanding the mechanism of radiopharmaceutical distribution in tumors. Furthermore, measures of characteristic length and advection time scale were computed. The presented spatiotemporal tumor transport model can analyze different physiological parameters affecting 177Lu-PSMA delivery.

Cerebral Protection in Trans-Catheter Aortic Valve Replacement: Review and Contemporary Assessment of Randomized Trial Data.

As the population has aged and as aortic valve therapies have evolved, the use of trans-catheter aortic valve replacement (TAVR) has grown dramatically over the past decade. A well-known complication of percutaneous cardiac intervention is embolic phenomena, and TAVR is among the highest risk procedures for clinical and subclinical stroke. As indications for TAVR expand to lower-risk and ultimately younger patients, the long-term consequences of stroke are amplified. Cerebral embolic protection (CEP) devices have taken a on unique preventative role following the Food and Drug Administration approval of the SentinelTM Cerebral Protection System (CPS). More recently, the PROTECTED TAVR study has spurred extensive debate in the neuro-cardiac community. In this review we describe the contemporary literature regarding stroke risk associated with TAVR, the history and role of CEP devices, a PROTECTED TAVR sub-group analysis, and implications for next steps in the field. Lastly, we explore the unique need for CEP in a younger TAVR population, as well as directions for future research.

Effect of twisting of intravitreal injections on ocular bio-mechanics: a novel insight to ocular surgery.

Although intravitreal (IVT) injections provide several advantages in treating posterior segment eye diseases, several associated challenges remain. The current study uses the finite element method (FEM) to highlight the effect of IVT needle rotation along the insertion axis on the reaction forces and deformation inside the eye. A comparison of the reaction forces at the eye's key locations has been made with and without rotation. In addition, a sensitivity analysis of various parameters, such as the needle's angular speed, insertion location, angle, gauge, shape, and intraocular pressure (IOP), has been carried out to delineate the individual parameter's effect on reaction forces during rotation. Results demonstrate that twisting the needle significantly reduces the reaction forces at the penetration location and throughout the needle travel length, resulting in quicker penetration. Moreover, ocular biomechanics are influenced by needle insertion location, angle, shape, size, and IOP. The reaction forces incurred by the patient may be reduced by using a bevel needle of the higher gauge when inserted close to the normal of the local scleral surface toward the orra serrata within the Pars Plana region. Results obtained from the current study can deepen the understanding of the twisting needle's interaction with the ocular tissue.

Image-based insilico investigation of hemodynamics and biomechanics in healthy and diabetic human retinas.

Retinal hemodynamics and biomechanics play a significant role in understanding the pathophysiology of several ocular diseases. However, these parameters are significantly affected due to changed blood vessel morphology ascribed to pathological conditions, particularly diabetes. In this study, an image-based computational fluid dynamics (CFD) model is applied to examine the effects of changed vascular morphology due to diabetes on blood flow velocity, vorticity, wall shear stress (WSS), and oxygen distribution and compare it with healthy. The 3D patient-specific vascular architecture of diabetic and healthy retina is extracted from Optical Coherence Tomography Angiography (OCTA) images and fundus to extract the capillary level information. Further, Fluid-structure interaction (FSI) simulations have been performed to compare the induced tissue stresses in diabetic and healthy conditions. Results illustrate that most arterioles possess higher velocity, vorticity, WSS, and lesser oxygen concentration than arteries for healthy and diabetic cases. However, an opposite trend is observed for venules and veins. Comparisons show that, on average, the blood flow velocity in the healthy case decreases by 42 % in arteries and 21 % in veins, respectively, compared to diabetic. In addition, the WSS and von Mises stress (VMS) in healthy case decrease by 49 % and 72 % in arteries and by 6 % and 28 % in veins, respectively, when compared with diabetic, making diabetic blood vessels more susceptible to wall rupture and tissue damage. The in-silico results may help predict the possible abnormalities region early, helping the ophthalmologists use these estimates as prognostic tools and tailor patient-specific treatment plans.

Convection-Enhanced Delivery of Antiangiogenic Drugs and Liposomal Cytotoxic Drugs to Heterogeneous Brain Tumor for Combination Therapy.

Although convection-enhanced delivery can successfully bypass the blood-brain barrier, its clinical performance remains disappointing. This is primarily attributed to the heterogeneous intratumoral environment, particularly the tumor microvasculature. This study investigates the combined convection-enhanced delivery of antiangiogenic drugs and liposomal cytotoxic drugs in a heterogeneous brain tumor environment using a transport-based mathematical model. The patient-specific 3D brain tumor geometry and the tumor's heterogeneous tissue properties, including microvascular density, porosity and cell density, are extracted from dynamic contrast-enhanced magnetic resonance imaging data. Results show that antiangiogenic drugs can effectively reduce the tumor microvascular density. This change in tissue structure would inhibit the fluid loss from the blood to prevent drug concentration from dilution, and also reduce the drug loss by blood drainage. The comparisons between different dosing regimens demonstrate that the co-infusion of liposomal cytotoxic drugs and antiangiogenic drugs has the advantages of homogenizing drug distribution, increasing drug accumulation, and enlarging the volume where tumor cells can be effectively killed. The delivery outcomes are susceptible to the location of the infusion site. This combination treatment can be improved by infusing drugs at higher microvascular density sites. In contrast, infusion at a site with high cell density would lower the treatment effectiveness of the whole brain tumor. Results obtained from this study can deepen the understanding of this combination therapy and provide a reference for treatment design and optimization that can further improve survival and patient quality of life.

Land Cover Change and Its Impact in Crop Yield: A Case Study from Western Nepal.

This study was conducted in Tanahun district of Gandaki Province, Nepal, to analyze the land cover change over two decades, the migration effect in land cover, and the impact caused in crop production by Rhesus macaque. Landsat TM/ETM+ for land use of 2000 and 2010 extracted by ICIMOD and Landsat 8 OLI/TIRS satellite images for land cover 2019 were downloaded from the USGS website. A purposive sample for household survey was carried out based on crops damaged by the monkey. Two hundred and fifty households were taken as samples. The Landsat images were analyzed by ArcGIS, and the social data were analyzed using SPSS and MS Excel. Land cover change data revealed increment of forest cover from 36.57% to 40.91% and drastic decrease in agriculture crops from 57.52% to 43.78% in the period of 20 years. The accuracy of the data showed overall classification accuracy of 86.11%, 81.08%, and 75% with overall kappa statistics 0.83, 0.77, and 0.74, respectively. The migration effect in the land cover was related to remittance and migrated members and found a significant positive relationship. Analyzing the trend of production with an increase in the forest cover, 21% decrease in paddy, 5% decrease in maize, and 26% decrease in millet were found as compared to the production in 2000. The econometric model concluded that the quantity of crop damage was negatively significant in relation to distance from forest and distance from water body while positively significant to distance from settlements and distance from owner's home. The quantity of crop damage was estimated 113.89 kg per household, and the cost was 78.82 USD. This study recommends active forest management; regular thinning, and weeding. Remittance generated should be invested in the agriculture field by the households. Damage relief should be made available for the damage cost by Rhesus macaque.

Ocular Fluid Mechanics and Drug Delivery: A Review of Mathematical and Computational Models.

The human eye is a complex biomechanical structure with a range of biomechanical processes involved in various physiological as well as pathological conditions. Fluid flow inside different domains of the eye is one of the most significant biomechanical processes that tend to perform a wide variety of functions and when combined with other biophysical processes play a crucial role in ocular drug delivery. However, it is quite difficult to comprehend the effect of these processes on drug transport and associated treatment experimentally because of ethical constraints and economic feasibility. Computational modeling on the other hand is an excellent means to understand the associated complexity between these aforementioned processes and drug delivery. A wide range of computational models specific to different types of fluids present in different domains of the eye as well as varying drug delivery modes has been established to understand the fluid flow behavior and drug transport phenomenon in an insilico manner. These computational models have been used as a non-invasive tool to aid ophthalmologists in identifying the challenges associated with a particular drug delivery mode while treating particular eye diseases and to advance the understanding of the biomechanical behavior of the eye. In this regard, the author attempts to summarize the existing computational and mathematical approaches proposed in the last two decades for understanding the fluid mechanics and drug transport associated with different domains of the eye, together with their application to modify the existing treatment processes.

Effect of aging on heat transfer, fluid flow and drug transport in anterior human eye: A computational study.

There are a lot of geometrical and morphological changes that happen in the human eye with age. Primary open-angle glaucoma, which is caused by the increase in intraocular pressure inside the anterior chamber of the eye is also associated with the physiological aging of the eye. Therefore, it is crucial to understand the effects of aging on drug delivery in the human eye when applied topically. Consequently, a numerical model of topical drug delivery for an aging human eye has been developed using commercial software COMSOL Multiphysics in the current study. Three different age groups (young, middle and old) have been considered and the changes in geometrical and tissue properties of different domains of the eye with age have been included in the numerical model. The effect of aging on heat transfer, aqueous humor flow, intraocular pressure and drug concentration in different domains and orientations of the eye have been investigated. Additionally, an attempt has been made to predict the best class of anti-glaucomatic treatment in silico that should be preferred to treat primary open-angle glaucoma effectively. Results illustrate that there is a decrease in the average corneal temperature and an increase in the temperature deviation across the cornea with age. Further, there is a decrease in the aqueous humor flow magnitude in the anterior chamber of the eye and an increase in intraocular pressure in the anterior chamber of older age groups, which leads to primary open-angle glaucoma. The reduced aqueous humor flow leads to increased drug concentration in the anterior chamber as well as iris and reduced drug concentration in the trabecular mesh of the older age groups, thereby affecting the treatment efficacy. Additionally, our simulated results demonstrate that anti-glaucomatic treatments should be more focused on treating the trabecular mesh rather than the ciliary body of the eye.

Managing thromboembolic risk from atrial fibrillation in patients with cancer: a role for nonpharmacologic approaches.

Atrial fibrillation (AF) in the setting of malignancy poses a unique challenge given the confluent pathologies and risks of current treatments. Oral anticoagulation is recommended to reduce the risk of systemic thromboembolism in high-risk individuals with AF. The 'Watchman' device for left atrial appendage closure has shown comparable efficacy compared with anticoagulation with warfarin; however, patients with cancer were not included in trials testing Watchman safety and efficacy. We present the current treatment approaches for the management of AF in patients with malignancy. We review contemporary guidelines and propose a novel clinical decision tree by which physicians can consider left atrial appendage closure in cancer patients, and at last, suggest future investigation that might further clarify the clinical benefit of this approach.

Numerical modeling of therapeutic lens drug delivery in the anterior human eye for the treatment of primary open-angle glaucoma.

A numerical model of drug delivery from a therapeutic lens in the anterior portion of the human eye has been developed for a more effective treatment plan of primary open-angle glaucoma. The numerical model takes into account the drug diffusion through the therapeutic lens along with heat transfer and aqueous humor flow in different orientations of the human eye (supine (two-dimensional) as well as standing (three-dimensional)). Results illustrate that the drug diffuses through the therapeutic lens to the cornea and is convected into the anterior chamber of the eye due to the temperature gradient across the eye. In addition, eye orientation significantly affects drug delivery with supine orientation providing better and uniform drug exposure in different target regions of the eye as compared to standing in the case of the therapeutic lens. Furthermore, a comparison of the therapeutic efficacy of the therapeutic lens has been done with topical administration and the drug uptake results from both the drug delivery modes have been validated with the experimental data reported in the literature. The developed model may help ophthalmologists to comprehend the transport and retention of different drugs in different domains and orientations of the human eye when administered through a therapeutic lens.

Comparison of transport of chemotherapeutic drugs in voxelized heterogeneous model of human brain tumor.

Systemic administration of chemotherapeutic drugs is widely used in the treatment of cancer. However, a good understanding of drug transport barriers that influence the treatment efficacy is still lacking. In this study, a voxelized numerical model based on dynamic contrast enhanced-magnetic resonance imaging (DCE-MRI) and computational fluid dynamics (CFD) is employed to study the transport and efficacy of three different chemotherapeutic drugs, namely methotrexate, doxorubicin and cisplatin in human brain tumors. DCE-MRI data provides realistic heterogeneous vasculature of the tumor, the permeability of tissue to contrast agent, interstitial volume fraction (porosity) of the tissue and patient-specific arterial input function (AIF). The permeability of tissue to aforementioned drugs is determined by correlating it with the permeability of tissue to the contrast agent. The model is employed to simulate drug concentration in the tissue and compare the effect of heterogeneous vasculature on the distribution of the drugs in the tumor. The drug accumulation is observed to be higher in high permeability areas initially, and in higher porosity areas at later times. Furthermore, it is observed that methotrexate remains in the interstitial space of the tumor in higher concentration for a longer duration as compared to other two drugs, facilitating more tumor cell killing.

Preferential Disruption of Prefrontal GABAergic Function by Nanomolar Concentrations of the α7nACh Negative Modulator Kynurenic Acid.

Increased concentrations of kynurenic acid (KYNA) in the prefrontal cortex (PFC) are thought to contribute to the development of cognitive deficits observed in schizophrenia. Although this view is consistent with preclinical studies showing a negative impact of prefrontal KYNA elevation on executive function, the mechanism underlying such a disruption remains unclear. Here, we measured changes in local field potential (LFP) responses to ventral hippocampal stimulation in vivo and conducted whole-cell patch-clamp recordings in brain slices to reveal how nanomolar concentrations of KYNA alter synaptic transmission in the PFC of male adult rats. Our data show that prefrontal infusions of KYNA attenuated the inhibitory component of PFC LFP responses, a disruption that resulted from local blockade of α7-nicotinic acetylcholine receptors (α7nAChR). At the cellular level, we found that the inhibitory action exerted by KYNA in the PFC occurred primarily at local GABAergic synapses through an α7nAChR-dependent presynaptic mechanism. As a result, the excitatory-inhibitory ratio of synaptic transmission becomes imbalanced in a manner that correlates highly with the level of GABAergic suppression by KYNA. Finally, prefrontal infusion of a GABAAR positive allosteric modulator was sufficient to overcome the disrupting effect of KYNA and normalized the pattern of LFP inhibition in the PFC. Thus, the preferential inhibitory effect of KYNA on prefrontal GABAergic transmission could contribute to the onset of cognitive deficits observed in schizophrenia because proper GABAergic control of PFC output is one key mechanism for supporting such cortical functions.SIGNIFICANCE STATEMENT Brain kynurenic acid (KYNA) is an astrocyte-derived metabolite and its abnormal elevation in the prefrontal cortex (PFC) is thought to impair cognitive functions in individuals with schizophrenia. However, the mechanism underlying the disrupting effect of KYNA remains unclear. Here we found that KYNA biases the excitatory-inhibitory balance of prefrontal synaptic activity toward a state of disinhibition. Such disruption emerges as a result of a preferential suppression of local GABAergic transmission by KYNA via presynaptic inhibition of α7-nicotinic acetylcholine receptor signaling. Therefore, the degree of GABAergic dysregulation in the PFC could be a clinically relevant contributing factor for the onset of cognitive deficits resulting from abnormal increases of cortical KYNA.

Increased epicardial adipose tissue is associated with coronary artery disease and major adverse cardiovascular events.

BACKGROUND: Increased-epicardial-adipose tissue (EAT) is associated with the presence and severity of subclinical-atherosclerosis. This study investigates the long-term clinical-outcome of subjects with and without increased-EAT. METHODS: Two hundred and forty-five subjects, aged 61 ± 9 years and 34% women underwent clinically-indicated computed-tomography-angiography (CTA), and body-surface-area adjusted EAT was measured and were followed prospectively. CTA-diagnosed coronary-artery-disease (CAD) was defined as obstructive (luminal-stenosis ≥ 50%), non-obstructive (luminal-stenosis: 1-49%) and zero-obstruction. Major-adverse-cardiac-event (MACE) was defined as myocardial-infarction or cardiovascular-death. RESULTS: EAT increased significantly from subjects with zero-obstruction-coronaries (93 ± 37 cm(3)/m(2)) to non-obstructive-CAD (132 ± 25 cm(3)/m(2)) to obstructive-CAD (145 ± 35 cm(3)/m(2)) (P = 0.01). During the 48-month follow-up, the event-rate was 8.6% (21). The event free survival-rate decreased significantly from 99% in the lowest-quartile to 86.6% in the highest-quartile of EAT. After adjustment for risk-factors, the hazard ratio of MACE was 1.4, 3.1 and 5.7 in lower mid-, upper mid- and highest-quartiles of EAT as compared to lowest-quartile of EAT (P < 0.05). CONCLUSION: Increased EAT is directly associated with CAD and predicts MACE independent of the age, gender and conventional-risk-factors.

Wdr68 requires nuclear access for craniofacial development.

Wdr68 is a highly conserved scaffolding protein required for craniofacial development and left-right asymmetry. A Ras-Map3k-Wdr68-Dyrk1 signaling relay may mediate these and other diverse signaling events important in development and disease. While the sub-cellular localization of Wdr68 has been shown to be dependent on that of its interaction partners, it is not clear where Wdr68 activity is required during development. Here we show that while a GFP-Wdr68 fusion functionally substituted for craniofacial development in the zebrafish, that a Nuclear Export Signal (NES) fusion protein (GFPNESWdr68) failed to support craniofacial development. As control for NES activity, we show that while GFP-Wdr68 exhibited a pan-cellular distribution in C2C12 cells, the GFPNESWdr68 fusion predominantly localized to the cell cytoplasm, as expected. Interestingly, while GFP-Wdr68 and RFP-Dyrk1a co-localized to the cell nucleus as expected based on the known sub-cellular localization for Dyrk1a, we found that the GFPNESWdr68 fusion redistributed RFP-Dyrk1a to the cell cytoplasm potentially disconnecting the Ras/Dyrk1 signal relay from further downstream targets. Consistent with a nuclear role in gene regulation, we also found that while a transcriptional activation domain fusion, CebpFlagWdr68, functionally substituted for endogenous Wdr68 for craniofacial development, that a transcriptional repression domain fusion, MadFlagWdr68, failed to support craniofacial development. Dyrk1b is required for myogenin (myog) expression in differentiating mouse C2C12 cells and here we report that wdr68 is also important for myog expression in differentiating C2C12 cells. Using a C2C12 cell myog promoter-reporter system, we found that Wdr68 overexpression increased reporter activity while moderate expression levels of MadFlagWdr68 interfered with reporter activity. Taken together, these findings support a nuclear role for Wdr68-containing complexes.