Advancing autologous CAR T-cell therapy through real-time patient health data integration: a simulation-based approach.

Autologous chimeric antigen receptor T-cell therapy presents promising treatment outcomes for various cancers. However, its potential is restrained by unique supply chain challenges, including dynamic patient health conditions and extended turnaround time. These challenges often lead to missed optimal treatment windows, impeding the effective delivery of life-saving treatments. This article presents SimPAC (simulation-based decision support for Patient-centric manufacturing of autologous cell therapies). SimPAC is designed to model and incorporate real-time patient health conditions into the supply chain decisions of autologous chimeric antigen receptor T-cell therapy. SimPAC integrates system dynamics and agent-based simulation techniques, facilitating the adaptation of manufacturing processes and production schedules based on real-time patient health conditions. SimPAC can model various patient disease progressions using parametric functions, nonparametric functions, or tabular data. Additionally, SimPAC offers easy configuration options to model various cell therapy supply chains. We provide two case studies to demonstrate the capabilities of SimPAC and highlight the benefits of patient-centric manufacturing, including improved survival rates and potential economic advantages. However, while the benefits are significant, our study also emphasizes the importance of balancing improved patient outcomes, economic viability and ethical considerations in the context of personalized medicine. SimPAC can be used to explore applications of this approach to diverse therapeutic contexts and supply chain configurations.

Transformative Insights: Break Up with Salt (BUWS) Program's Short-Term Influence on Hypertension Risk Factors.

Break Up with Salt (BUWS) is a four-session community-based nutrition education program aimed at reducing key controllable hypertension risk factors. This pilot study utilized a pre-post survey design to assess short-term outcomes on food behaviors (including DASH diet eating patterns), physical activity, and overall well-being, in two groups of participants. The first "pilot" group (n = 25) completed a comprehensive, 16-item survey; the second "abbreviated" group (n = 27) completed a 5-item survey. The pilot group experienced improvements in whole grain (p = 0.04), sweetened beverage consumption, watching/reducing sodium (p = 0.04) and fat (p = 0.05) consumption, and time spent sitting (p = 0.04). The abbreviated group improved confidence in using food labels (p = 0.02), following the DASH diet (p < 0.01), preparing food without salt (p = 0.03), selecting lower sodium items when eating out (p = 0.04), and making a positive lifestyle change (p = 0.01). The BUWS program provides information and teaches strategies to manage or prevent hypertension. By effectively improving diet and food behaviors, BUWS has the potential to reduce hypertension risk factors and improve the general health of participants.

Weight and protozoa number but not bacteria diversity are associated with successful pair formation of dealates in the Formosan subterranean termite, Coptotermes formosanus.

New colonies of Formosan subterranean termites are founded by monogamous pairs. During swarming season, alates (winged reproductives) leave their parental colony. After swarming, they drop to the ground, shed their wings, and male and female dealates find suitable nesting sites where they mate and become kings and queens of new colonies. The first generation of offspring is entirely dependent on the nutritional resources of the founder pair consisting of the fat and protein reserves of the dealates and their microbiota, which include the cellulose-digesting protozoa and diverse bacteria. Since termite kings and queens can live for decades, mate for life and colony success is linked to those initial resources, we hypothesized that gut microbiota of founders affect pair formation. To test this hypothesis, we collected pairs found in nest chambers and single male and female dealates from four swarm populations. The association of three factors (pairing status, sex of the dealates and population) with dealate weights, total protozoa, and protozoa Pseudotrichonympha grassii numbers in dealate hindguts was determined. In addition, Illumina 16S rRNA gene sequencing and the QIIME2 pipeline were used to determine the impact of those three factors on gut bacteria diversity of dealates. Here we report that pairing status was significantly affected by weight and total protozoa numbers, but not by P. grassii numbers and bacteria diversity. Weight and total protozoa numbers were higher in paired compared to single dealates. Males contained significantly higher P. grassii numbers and bacteria richness and marginally higher phylogenetic diversity despite having lower weights than females. In conclusion, this study showed that dealates with high body weight and protozoa numbers are more likely to pair and become colony founders, probably because of competitive advantage. The combined nutritional resources provided by body weight and protozoa symbionts of the parents are important for successful colony foundation and development.

Biomarker-based precision dose finding for immunotherapy combined with radiotherapy.

Recent success of sequential administration of immunotherapy following radiotherapy (RT), often referred to as immunoRT, has sparked the urgent need for novel clinical trial designs to accommodate the unique features of immunoRT. For this purpose, we propose a Bayesian phase I/II design for immunotherapy administered after standard-dose RT to identify the optimal dose that is personalized for each patient according to his/her measurements of PD-L1 expression at baseline and post-RT. We model the immune response, toxicity, and efficacy as functions of dose and patient's baseline and post-RT PD-L1 expression profile. We quantify the desirability of the dose using a utility function and propose a two-stage dose-finding algorithm to find the personalized optimal dose. Simulation studies show that our proposed design has good operating characteristics, with a high probability of identifying the personalized optimal dose.

A Bayesian phase I/II design to determine subgroup-specific optimal dose for immunotherapy sequentially combined with radiotherapy.

Sequential administration of immunotherapy following radiotherapy (immunoRT) has attracted much attention in cancer research. Due to its unique feature that radiotherapy upregulates the expression of a predictive biomarker for immunotherapy, novel clinical trial designs are needed for immunoRT to identify patient subgroups and the optimal dose for each subgroup. In this article, we propose a Bayesian phase I/II design for immunotherapy administered after standard-dose radiotherapy for this purpose. We construct a latent subgroup membership variable and model it as a function of the baseline and pre-post radiotherapy change in the predictive biomarker measurements. Conditional on the latent subgroup membership of each patient, we jointly model the continuous immune response and the binary efficacy outcome using plateau models, and model toxicity using the equivalent toxicity score approach to account for toxicity grades. During the trial, based on accumulating data, we continuously update model estimates and adaptively randomize patients to admissible doses. Simulation studies and an illustrative trial application show that our design has good operating characteristics in terms of identifying both patient subgroups and the optimal dose for each subgroup.

Varying coefficient frailty models with applications in single molecular experiments.

Motivated by an analysis of single molecular experiments in the study of T-cell signaling, a new model called varying coefficient frailty model with local linear estimation is proposed. Frailty models have been extensively studied, but extensions to nonconstant coefficients are limited to spline-based methods that tend to produce estimation bias near the boundary. To address this problem, we introduce a local polynomial kernel smoothing technique with a modified expectation-maximization algorithm to estimate the unknown parameters. Theoretical properties of the estimators, including their unbiased property near the boundary, are derived along with discussions on the asymptotic bias-variance trade-off. The finite sample performance is examined by simulation studies, and comparisons with existing spline-based approaches are conducted to show the potential advantages of the proposed approach. The proposed method is implemented for the analysis of T-cell signaling. The fitted varying coefficient model provides a rigorous quantification of an early and rapid impact on T-cell signaling from the accumulation of bond lifetime, which can shed new light on the fundamental understanding of how T cells initiate immune responses.

Research of electrosurgical unit with novel antiadhesion composite thin film for tumor ablation: Microstructural characteristics, thermal conduction properties, and biological behaviors.

The objective of this study was to use surface functionalization to evaluate the antiadhesion property and thermal injury effects on the liver when using a novel electrosurgical unit with nanostructured-doped diamond-like carbon (DLC-Cu) thin films for tumor ablations. The physical and chemical properties of DLC-Cu thin films were characterized by contact angle goniometer, scanning electron microscope, and transmission electron microscope. Three-dimensional (3D) hepatic models were reconstructed using magnetic resonance imaging to simulate a clinical electrosurgical operation. The results indicated a significant increase of the contact angle on the nanostructured DLC-Cu thin films, and the antiadhesion properties were also observed in an animal model. Furthermore, the surgical temperature in the DLC-Cu electrosurgical unit was found to be significantly lower than the untreated unit when analyzed using 3D models and thermal images. In addition, DLC-Cu electrodes caused a relatively small injury area and lateral thermal effect. The results indicated that the nanostructured DLC-Cu thin film coating reduced excessive thermal injury and tissue adherence effect in the liver.

Effect of Anti-Sticking Nanostructured Surface Coating on Minimally Invasive Electrosurgical Device in Brain.

The purpose of the present study was to examine the extent of thermal injury in the brain after the use of a minimally invasive electrosurgical device with a nanostructured copper-doped diamond-like carbon (DLC-Cu) surface coating. To effectively utilize an electrosurgical device in clinical surgery, it is important to decrease the thermal injury to the adjacent tissues. The surface characteristics and morphology of DLC-Cu thin film was evaluated using a contact angle goniometer, scanning electron microscopy, and atomic force microscopy. Three-dimensional biomedical brain models were reconstructed using magnetic resonance images to simulate the electrosurgical procedure. Results indicated that the temperature was reduced significantly when a minimally invasive electrosurgical device with a DLC-Cu thin film coating (DLC-Cu-SS) was used. Temperatures decreased with the use of devices with increasing film thickness. Thermographic data revealed that surgical temperatures in an animal model were significantly lower with the DLC-Cu-SS electrosurgical device compared to an untreated device. Furthermore, the DLC-Cu-SS device created a relatively small region of injury and lateral thermal range. As described above, the biomedical nanostructured film reduced excessive thermal injury with the use of a minimally invasive electrosurgical device in the brain.

Biomedical electrosurgery devices containing nanostructure for minimally invasive surgery: reduction of thermal injury and acceleration of wound healing for liver cancer.

The aim of the present study was to investigate the thermal injury in the liver after a minimally invasive electrosurgery technique with a copper-doped diamond-like carbon (DLC-Cu) surface coating. To effectively utilize electrosurgery in a clinical caner setting, it is necessary to suppress the thermal injury to adjacent tissues. The surface morphologies of DLC-Cu thin films were characterized using scanning electron microscopy and transmission electron microscopy. Three-dimensional liver models were reconstructed using magnetic resonance imaging to simulate the electrosurgical procedure. Our results indicated that the temperature decreased significantly when minimally electrosurgery with nanostructured DLC-Cu thin films was used, and that it continued to decrease with increasing film thickness. In an animal model, thermography revealed that the surgical temperature was significantly lower in the minimally invasive electrosurgery with DLC-Cu thin film (DLC-Cu-SS) compared to untreated electrosurgery. In addition, DLC-Cu-SS created a relatively small thermal injury area and lateral thermal effect. These results indicated that the biomedical nanostructure coating reduced excessive thermal injury, and uniformly distributed temperature in the liver.

Effects of antibacterial nanostructured composite films on vascular stents: hemodynamic behaviors, microstructural characteristics, and biomechanical properties.

The purpose of this research was to investigate stresses resulting from different thicknesses and compositions of hydrogenated Cu-incorporated diamond-like carbon (a-C:H/Cu) films at the interface between vascular stent and the artery using three-dimensional reversed finite element models (FEMs). Blood flow velocity variation in vessels with plaques was examined by angiography, and the a-C:H/Cu films were characterized by transmission electron microscopy to analyze surface morphology. FEMs were constructed using a computer-aided reverse design system, and the effects of antibacterial nanostructured composite films in the stress field were investigated. The maximum stress in the vascular stent occurred at the intersections of net-like structures. Data analysis indicated that the stress decreased by 15% in vascular stents with antibacterial nanostructured composite films compared to the control group, and the stress decreased with increasing film thickness. The present results confirmed that antibacterial nanostructured composite films improve the biomechanical properties of vascular stents and release abnormal stress to prevent restenosis. The results of the present study offer the clinical benefit of inducing superior biomechanical behavior in vascular stents.

Follow-up study of dental implants with bioactive oxide films on bone tissue healing and osseointegration: clinical radiography and bone quality analysis.

OBJECTIVE: The purpose of this study was to investigate osseointegration and bone stress resulted during the first 3 months after the installation of functional implants modified with bioactive oxide. METHODS: Several studies have investigated finite element models for dental implants; however, only a few have examined a model for the implants during different stages of osseointegration. In this study, mandible models were reconstructed using computer tomographic data, and bone qualities and stress distributions were investigated as well. RESULTS: Bone quality increased rapidly within the 3-month bone healing time. Data analysis indicated that the bone stresses increased with the progress of osseointegration, and the maximum stresses were obtained at the position around the first screw. CONCLUSION: The results confirmed that functional films could improve the biomechanical properties of the implants and promote the initial bone stability. Furthermore, potential clinical benefit can be obtained due to the inducing superior biomechanical behavior in dental implants.

An Immunomodulatory Protein (Ling Zhi-8) from a Ganoderma lucidum Induced Acceleration of Wound Healing in Rat Liver Tissues after Monopolar Electrosurgery.

The purpose of this study was to investigate the effect of an immunomodulatory protein (Ling Zhi-8, LZ-8) on wound healing in rat liver tissues after monopolar electrosurgery. Animals were sacrificed for evaluations at 0, 3, 7, and 28 days postoperatively. It was found that the wound with the LZ-8 treatment significantly increases wound healing. Western blot analysis clearly indicated that the expression of NF-κB was decreased at 3, 7, and 28 days when liver tissues were treated with LZ-8. Moreover, caspase-3 activity of the liver tissue also significantly decreases at 7 and 28 days, respectively. DAPI staining and TUNEL assays revealed that only a minimal dispersion of NF-κB was found on the liver tissue treated with LZ-8 at day 7 as compared with day 3 and tissues without LZ-8 treatment. Similarly, apoptosis was decreased on liver tissues treated with LZ-8 at 7 days when compared to the control (monopolar electrosurgery) tissues. Therefore, the analytical results demonstrated that LZ-8 induced acceleration of wound healing in rat liver tissues after monopolar electrosurgery.

Effect of recombinant human bone morphogenetic protein-2 and Ling Zhi-8 on osteogenesis: a comparative study using a rabbit sinus model.

PURPOSE: This study evaluated the osteogenetic capability of Ling Zhi-8 (LZ-8; a protein purified from traditional Chinese medicine [lingzhi]) compared with recombinant human bone morphogenic protein-2 (rhBMP-2) in a standardized bony defect using a rabbit sinus model. MATERIALS AND METHODS: Twelve male New Zealand white rabbits (18 to 24 weeks old, 3.3 to 3.8 kg) were included in the study. Implants of normal saline 0.1 mg, rhBMP-2 0.1 mg, and LZ-8 0.1 mg were each mixed with a uniform biodegradable polyurethane-based material (Nasopore). The implants were inserted in a standardized bony defect of the nasal bone created by a 2.5-mm trephine bur. The rabbits were sacrificed at 1, 2, 4, and 8 weeks postoperatively. Volume computerized tomographic and histomorphometric examinations were used to evaluate the quantity and quality of regenerated bone. RESULTS: At postoperative week 4, radiography showed that the new bone volume was significantly larger in the rhBMP-2 group compared with the LZ-8 group (P = .041) and the control group (P = .015). Histomorphometrically, better wound healing of the rhBMP-2 group was found during the healing phase compared with the other 2 groups. CONCLUSION: The biomaterial implants using rhBMP-2 and LZ-8 had good biocompatibility and osteogenetic capabilities in the rabbit sinus model. Bone healing in rhBMP-2-treated defects was excellent and showed a significant difference compared with LZ-8. However, LZ-8-treated defects also exhibited bone regeneration, and this traditional Chinese medicine may possess osteogenic potential. Further investigations of the mechanism and application of this protein in osteogenesis are needed.

Development of the novel ferrous-based stainless steel for biomedical applications, part I: high-temperature microstructure, mechanical properties and damping behavior.

This research investigated the high-temperature microstructure, mechanical properties, and damping behavior of Fe-9 Al-30 Mn-1C-5 Co (wt.%) alloy by means of electron microscopy, experimental model analysis, and hardness and tensile testing. Subsequent microstructural transformation occurred when the alloy under consideration was subjected to heat treatment in the temperature range of 1000-1150 °C: γ → (γ+κ). The κ-phase carbides had an ordered L'1(2)-type structure with lattice parameter a = 0.385 nm. The maximum yield strength (σ(y)), hardness, elongation, and damping coefficient of this alloy are 645 MPa, Hv 292, ~54%, and 178.5 × 10(-4), respectively. These features could be useful in further understanding the relationship between the biocompatibility and the wear and corrosion resistance of the alloy, so as to allow the development of a promising biomedical material.

GDF-5 is suppressed by IL-1beta and enhances TGF-beta3-mediated chondrogenic differentiation in human rheumatoid fibroblast-like synoviocytes.

OBJECTIVE: To investigate the expression of growth differentiation factor-5 (GDF-5) in chondrocytes (HC) and fibroblast-like synoviocytes (FLS) from humans with rheumatoid arthritis (RA) when stimulated with proinflammatory cytokines and to explore whether GDF-5 plays a role in regulating the differentiation of FLS-RA into chondrocytes. METHODS: Expression of GDF-5 in synovium and cartilage in RA and osteoarthritis (OA) was assessed by immunohistochemistry. GDF-5 production in FLS-RA and HC-RA was examined through real-time quantitative RT-PCR (Q-PCR) and western blotting. Expressions of GDF-associated receptors on FLS-RA were determined by semiquantitative-PCR, and MTT assay was used to study the effects on FLS-RA proliferation. Effect of GDF-5 and TGF-beta3 on in vitro chondrogenic ability of FLS-RA was investigated using pellet-culture system, Q-PCR and histological analysis. RESULTS: Immunohistochemical analysis demonstrated that GDF-5 expression in the synovium and cartilage from joints of RA patients was much lower than that of OA patients. Addition of IL-1beta or TNF-alpha appeared to downregulate the expression of GDF-5 in HC-RA and FLS-RA. Inhibition of GDF-5 expression by IL-1beta in RA-FLS was attenuated by pretreatment with MEK1/2 inhibitor. GDF-5-associated receptors were expressed in FLS-RA, but GDF-5 had no effect on FLS-RA proliferation. GDF-5 had a strong chondrogenic-promoting effect on TGF-beta3-induced chondrocyte differentiation in FLS-RA. CONCLUSIONS: GDF-5 is expressed in FLS-RA and HC-RA, and its expression is strongly downregulated by proinflammatory cytokines. MEK-ERK pathway is a negative regulator of GDF-5 expression in FLS-RA. In FLS-RA, synergy between GDF-5 and TGF-beta3 enhances chondrogenesis. Anti-inflammatory drugs combined with GDF-5 might be a new therapeutic treatment for RA.

Developmental changes in pharyngeal airway depth and hyoid bone position from childhood to young adulthood.

OBJECTIVE: (1) To test the hypothesis that there are no developmental changes in the pharyngeal airway depth and hyoid bone position from childhood to adulthood in normal Taiwanese persons, (2) to identify any sexual dimorphism, and (3) to find the predictive value of selective variables for the hyoid bone position. MATERIALS AND METHODS: Lateral cephalometric radiographs of 239 normal Taiwanese (132 females and 107 males; aged 7-27 years) were separated into three stages according to dental age. Twenty-three linear and 20 angular measurements were made in all subjects. Sexual dimorphism was analyzed by Student's t-test. Analysis of variance was used to compare the three stages in both genders. A stepwise regression analysis was carried out to predict the hyoid bone position. The level of significance for all analyses was set at P < .05. RESULTS: The pharyngeal airway depth increased from the mixed dentition stage to the permanent dentition stage in both genders. There was sexual dimorphism in the lower pharyngeal airway depth. The hyoid bone position showed an obvious difference in the permanent dentition stages between genders. The vertical position of the hyoid bone was associated with the mandibular morphology and position, but the relationship in males was reversed compared with that in females. CONCLUSIONS: The hypothesis was rejected. There are developmental changes in the pharyngeal airway depth and hyoid position from childhood to young adulthood. Sexual dimorphism appeared in the lower pharyngeal airway and the direction of change in the vertical position of the hyoid bone.

Bond strength of various bracket base designs.

To determine the influence of various bracket base designs on bond strength and debond interface, 6 types of metal interlock brackets of different sizes and with different base designs were evaluated. The bracket base types and mesh sizes tested were as follows: retention groove base (Dynalock, Unitek, Monrovia, Calif), circular concave base (Accuarch appliance Formula-R, Tomy, Tokyo, Japan), double mesh with 5.1 x 10(-2) mm2 mesh size (Ultratrimm, Dentaurum, Ispringen, Germany), double mesh, 3.1 x 10(-2) mm2 (Minidiagonali Roth, Leone, Florence, Italy), double mesh, 3.1 x 10(-2) mm2 (Tip-edge Rx-I, TP Orthodontics, LaPorte Ind), and double mesh, 2.9 x 10(-2) mm2 (Mini Diamond, Ormco, Glendora, Calif). The Unitek bracket is cast in 1 piece; the other brackets are welded together. Brackets were bonded to human teeth and then debonded on a testing machine. The debond interface was recorded and analyzed with scanning electron microscopy and energy-dispersive x-ray spectrometry, and the distribution of interfaces was determined. The ranking of bond strength of individual bases (kg/base) from highest to lowest was Tomy, Dentaurum, Unitek, Leone, TP Orthodontics, and Ormco. The ranking of bonding strength per area squared MPa from highest to lowest was Tomy, Dentaurum, Leone, Unitek, TP Orthodontics, and Ormco. Debond in interfaces occurred between the bracket and resin, within the resin, or between the resin and enamel. The most debonded interfaces were between the bracket and resin and between the resin and enamel. The Tomy bracket, with its circular concave base, produced greater bond strength than did the mesh-based brackets; among the mesh-based brackets, Dentaurum, with the larger mesh size, produced greater bond strength than the brackets with smaller mesh sizes. The Unitek bracket, with its 1-piece cast base with retention grooves, ranked in the midrange of bond strength.

Early detection of implant healing process using resonance frequency analysis.

In this study, in vitro and in vivo models were adopted for assessing the application of resonance frequency analysis (RFA) in the early detection of implant stability. In the in vitro tests, RF values of implants placed in bone block with predrilled cavities of 3.75 and 5.0 mm were measured and compared. Stone was used to fill the inter-space between implants and the bone blocks. Our results showed that poor initial stability conditions contributed to a lower initial RF (IRF) value (5.41+/-0.32 kHz) and a longer simulated healing period (41 min) than that of well-fitted conditions (9.63+/-0.34 kHz for IRF, 14 min for the simulated healing period, P<0.05). To validate such in vitro tests, animal models were also performed. Implants were placed in the left tibias of six rabbits using a general surgery procedure. The modal testing method was used to test the RF values of the implants. The RF values of the implants increased significantly (P<0.05) during the healing period and reached a plateau when the implant-bone interface was united. The variations of RF values of the testing implants showed a similar trend to the results of in vitro tests, i.e., implants with higher initial RF values had shorter simulated healing times. Based on these findings, we concluded that RFA is a reliable and accurate method for early assessment of the osseointegration process.