Creating an Innovative Artificial Intelligence-Based Technology (TCRact) for Designing and Optimizing T Cell Receptors for Use in Cancer Immunotherapies: Protocol for an Observational Trial.

BACKGROUND: Cancer continues to be the leading cause of mortality in high-income countries, necessitating the development of more precise and effective treatment modalities. Immunotherapy, specifically adoptive cell transfer of T cell receptor (TCR)-engineered T cells (TCR-T therapy), has shown promise in engaging the immune system for cancer treatment. One of the biggest challenges in the development of TCR-T therapies is the proper prediction of the pairing between TCRs and peptide-human leukocyte antigen (pHLAs). Modern computational immunology, using artificial intelligence (AI)-based platforms, provides the means to optimize the speed and accuracy of TCR screening and discovery. OBJECTIVE: This study proposes an observational clinical trial protocol to collect patient samples and generate a database of pHLA:TCR sequences to aid the development of an AI-based platform for efficient selection of specific TCRs. METHODS: The multicenter observational study, involving 8 participating hospitals, aims to enroll patients diagnosed with stage II, III, or IV colorectal cancer adenocarcinoma. RESULTS: Patient recruitment has recently been completed, with 100 participants enrolled. Primary tumor tissue and peripheral blood samples have been obtained, and peripheral blood mononuclear cells have been isolated and cryopreserved. Nucleic acid extraction (DNA and RNA) has been performed in 86 cases. Additionally, 57 samples underwent whole exome sequencing to determine the presence of somatic mutations and RNA sequencing for gene expression profiling. CONCLUSIONS: The results of this study may have a significant impact on the treatment of patients with colorectal cancer. The comprehensive database of pHLA:TCR sequences generated through this observational clinical trial will facilitate the development of the AI-based platform for TCR selection. The results obtained thus far demonstrate successful patient recruitment and sample collection, laying the foundation for further analysis and the development of an innovative tool to expedite and enhance TCR selection for precision cancer treatments. TRIAL REGISTRATION: ClinicalTrials.gov NCT04994093; https://clinicaltrials.gov/ct2/show/NCT04994093. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/45872.

Fluid structure interaction versus rigid-wall approach in the study of the symptomatic stenosed carotid artery: Importance of wall compliance and resilience of loose connective tissue.

The purpose of this paper is to demonstrate the importance of a compliant wall approach in modeling of non-Newtonian and non-physiological blood flows. A case study of a stenosed and symptomatic carotid bifurcation was considered to show the influence of the wall-resilience assumption on the flow parameters obtained with numerical simulations. Patient-specific data concerning the geometry and flow conditions were collected and used to carry out two-way coupled fluid structure interaction simulations of the pulsatile blood flow through carotid artery. The wall compliance was considered separately as related to the wall-elasticity and as associated with the reaction of the loose connective tissue surrounding the carotid bifurcation. The obtained hemodynamic parameters were compared to those which were found in rigid-wall simulations. The difference between the results obtained for rigid-wall and compliant-wall approaches for the peak-systolic area-averaged wall shear stress achieved 35%, whereas the difference between the time-averaged local vorticity and shear strain reached, respectively, 42% and 43%. The influence of the highly resilient wall on the monitored hemodynamic parameters was significant even if time-averaged values are compared, which suggests that these metrics are considerably overestimated if the wall compliance is not considered. Moreover, the findings show that the mechanical response of the loose connective tissue cannot be neglected in blood flow simulations. Additionally, this study indicates that stiffening of the arterial wall due to atherosclerosis significantly rises hemodynamic parameters. This explains the therapeutic benefits of surgical removal of plaque lesions formed in the carotid bifurcation (endarterectomy).

Screening test for extracranial carotid lesions' detection in patients of an outpatient vascular clinic.

Purpose The objective of the study was to evaluate the frequency and severity of atherosclerotic lesions in extracranial sections of carotid arteries and to determine the level of the correlation between these lesions and symptoms of cerebral ischemia. Secondly, to identify the most common risk factors of ischaemic stroke occurrence in population of patients of vascular outpatient clinic. Material and Methods Prospective study was conducted on a group of 1,000 people (217 women and 783 men), aged 50 to 86 years, the average age was 62 years (± 9.95). Results Atherosclerotic lesions of carotid arteries were observed in 670 examined people (67%). In 63 cases (6.3%) carotid artery occlusion was revealed. Patients with symptomatic carotid artery stenosis more frequently were addicted to cigarettes and suffered from hypertension in comparison to asymptomatic group. A statistically significant correlation between the TIA or ischemic stroke and smoking were noticed, as well as between TIA/ischemic stroke and hypertension Conclusions Among patients with atherosclerosis of peripheral arteries atherosclerotic lesions in the extracranial carotid sections occur with a high frequency. Statistically significant differences in the incidence and severity of atherosclerotic lesions in the carotid arteries were observed in this group. A statistically significant correlation was revealed between the prevalence and severity of atherosclerosis in the carotid arteries in symptomatic patients and smoking and hypertension. Performing screening in patients with atherosclerosis of the abdominal aorta and/or lower limb arteries may detect significant carotid artery stenosis, requiring surgical intervention.