Development of a time-resolved immunochromatographic test strip for rapid and quantitative determination of GFAP in serum.

Glial fibrillary acidic protein (GFAP) in serum has been shown as a biomarker of traumatic brain injury (TBI) which is a significant global public health concern. Accurate and rapid detection of serum GFAP is critical for TBI diagnosis. In this study, a time-resolved fluorescence immunochromatographic test strip (TRFIS) was proposed for the quantitative detection of serum GFAP. This TRFIS possessed excellent linearity ranging from 0.05 to 2.5 ng/mL for the detection of serum GFAP and displayed good linearity (Y = 598723X + 797198, R2 = 0.99), with the lowest detection limit of 16 pg/mL. This TRFIS allowed for quantitative detection of serum GFAP within 15 min and showed high specificity. The intra-batch coefficient of variation (CV) and the inter-batch CV were both < 4.0%. Additionally, this TRFIS was applied to detect GFAP in the serum samples from healthy donors and patients with cerebral hemorrhage, and the results of TRFIS could efficiently discern the patients with cerebral hemorrhage from the healthy donors. Our developed TRFIS has the characteristics of high sensitivity, high accuracy, and a wide linear range and is suitable for rapid and quantitative determination of serum GFAP on-site.

A 3D spheroid model of quadruple cell co-culture with improved liver functions for hepatotoxicity prediction.

Drug-induced liver injury (DILI) is one of the major concerns during drug development. Wide acceptance of the 3 R principles and the innovation of in-vitro techniques have introduced various novel model options, among which the three-dimensional (3D) cell spheroid cultures have shown a promising prospect in DILI prediction. The present study developed a 3D quadruple cell co-culture liver spheroid model for DILI prediction via self-assembly. Induction by phorbol 12-myristate 13-acetate at the concentration of 15.42 ng/mL for 48 hours with a following 24-hour rest period was used for THP-1 cell differentiation, resulting in credible macrophagic phenotypes. HepG2 cells, PUMC-HUVEC-T1 cells, THP-1-originated macrophages, and human hepatic stellate cells were selected as the components, which exhibited adaptability in the designated spheroid culture conditions. Following establishment, the characterization demonstrated the competence of the model in long-term stability reflected by the maintenance of morphology, viability, cellular integration, and cell-cell junctions for at least six days, as well as the reliable liver-specific functions including superior albumin and urea secretion, improved drug metabolic enzyme expression and CYP3A4 activity, and the expression of MRP2, BSEP, and P-GP accompanied by the bile acid efflux transport function. In the comparative testing using 22 DILI-positive and 5 DILI-negative compounds among the novel 3D co-culture model, 3D HepG2 spheroids, and 2D HepG2 monolayers, the 3D culture method significantly enhanced the model sensitivity to compound cytotoxicity compared to the 2D form. The novel co-culture liver spheroid model exhibited higher overall predictive power with margin of safety as the classifying tool. In addition, the non-parenchymal cell components could amplify the toxicity of isoniazid in the 3D model, suggesting their potential mediating role in immune-mediated toxicity. The proof-of-concept experiments demonstrated the capability of the model in replicating drug-induced lipid dysregulation, bile acid efflux inhibition, and α-SMA upregulation, which are the key features of liver steatosis and phospholipidosis, cholestasis, and fibrosis, respectively. Overall, the novel 3D quadruple cell co-culture spheroid model is a reliable and readily available option for DILI prediction.

Quantification of functional hemodynamics in aortic valve disease using cardiac computed tomography angiography.

BACKGROUND AND OBJECTIVE: Cardiac computed tomography angiography (CTA) is the preferred modality for preoperative planning in aortic valve stenosis. However, it cannot provide essential functional hemodynamic data, specifically the mean transvalvular pressure gradient (MPG). This study aims to introduce a computational fluid dynamics (CFD) approach for MPG quantification using cardiac CTA, enhancing its diagnostic value. METHODS: Twenty patients underwent echocardiography, cardiac CTA, and invasive catheterization for pressure measurements. Cardiac CTA employed retrospective electrocardiographic gating to capture multi-phase data throughout the cardiac cycle. We segmented the region of interest based on mid-systolic phase cardiac CTA images. Then, we computed the average flow velocity into the aorta as the inlet boundary condition, using variations in end-diastolic and end-systolic left ventricular volume. Finally, we conducted CFD simulations using a steady-state model to obtain pressure distribution within the computational domain, allowing for the derivation of MPG. RESULTS: The mean value of MPG, measured via invasive catheterization (MPGInv), echocardiography (MPGEcho), and cardiac CTA (MPGCT), were 51.3 ± 28.4 mmHg, 44.8 ± 19.5 mmHg, and 55.8 ± 25.6 mmHg, respectively. In comparison to MPGInv, MPGCT exhibited a higher correlation of 0.91, surpassing that of MPGEcho, which was 0.82. Moreover, the limits of agreement for MPGCT ranged from -27.7 to 18.7, outperforming MPGEcho, which ranged from -40.1 to 18.0. CONCLUSIONS: The proposed method based on cardiac CTA enables the evaluation of MPG for aortic valve stenosis patients. In future clinical practice, a single cardiac CTA examination can comprehensively assess both the anatomical and functional hemodynamic aspects of aortic valve disease.

Bimetallic nanoparticles as cascade sensitizing amplifiers for low-dose and robust cancer radio-immunotherapy.

Radiotherapy (RT) is one of the most feasible and routinely used therapeutic modalities for treating malignant tumors. In particular, immune responses triggered by RT, known as radio-immunotherapy, can partially inhibit the growth of distantly spreading tumors and recurrent tumors. However, the safety and efficacy of radio-immunotherapy is impeded by the radio-resistance and poor immunogenicity of tumor. Herein, we report oxaliplatin (IV)-iron bimetallic nanoparticles (OXA/Fe NPs) as cascade sensitizing amplifiers for low-dose and robust radio-immunotherapy. The OXA/Fe NPs exhibit tumor-specific accumulation and activation of OXA (II) and Fe2+ in response to the reductive and acidic microenvironment within tumor cells. The cascade reactions of the released metallic drugs can sensitize RT by inducing DNA damage, increasing ROS and O2 levels, and amplifying the immunogenic cell death (ICD) effect after RT to facilitate potent immune activation. As a result, OXA/Fe NPs-based low-dose RT triggered a robust immune response and inhibited the distant and metastatic tumors effectively by a strong abscopal effect. Moreover, a long-term immunological memory effect to protect mice from tumor rechallenging is observed. Overall, the bimetallic NPs-based cascade sensitizing amplifier system offers an efficient radio-immunotherapy regimen that addresses the key challenges.

Potato glycoside alkaloids exhibit antifungal activity by regulating the tricarboxylic acid cycle pathway of Fusarium solani.

Fusarium solani is a pathogenic fungus that causes significant harm, leading to crop yield reduction, fruit quality reduction, postharvest decay, and other diseases. This study used potato glycoside alkaloids (PGA) as inhibitors to investigate their effects on the mitochondrial structure and tricarboxylic acid (TCA) cycle pathway of F. solani. The results showed that PGA could inhibit the colony growth of F. solani (54.49%), resulting in the disappearance of the mitochondrial membrane and the loss of contents. PGA significantly decreased the activities of aconitase (ACO), isocitrate dehydrogenase (IDH), α-ketoglutarate dehydrogenase (α-KGDH), succinate dehydrogenase (SDH), fumarase (FH), malate dehydrogenase (MDH), succinyl-CoA synthetase (SCS), and increased the activity of citrate synthase (CS) in F. solani. After PGA treatment, the contents of acetyl coenzyme A (CoA), citric acid (CA), malic acid (L-MA), and α-ketoglutaric acid (α-KG) in F. solani were significantly decreased. The contents of isocitric acid (ICA), succinyl coenzyme A (S-CoA), succinic acid (SA), fumaric acid (FA), and oxaloacetic acid (OA) were significantly increased. Transcriptomic analysis showed that PGA could significantly affect the expression levels of 19 genes related to TCA cycle in F. solani. RT-qPCR results showed that the expression levels of ACO, IDH, α-KGDH, and MDH-related genes were significantly down-regulated, and the expression levels of SDH and FH-related genes were significantly up-regulated, which was consistent with the results of transcriptomics. In summary, PGA can achieve antifungal effects by reducing the tricarboxylic acid cycle's flow and regulating key genes' expression levels. This study reveals the antifungal mechanism of PGA from the perspective of TCA cycle, and provides a theoretical basis for the development and application of PGA as a biopesticide.

High Spatial Resolution 2D Imaging of Current Density and Pressure for Graphene Devices under High Pressure Using Nitrogen-Vacancy Centers in Diamond.

Current density imaging is helpful for discovering interesting electronic phenomena and understanding carrier dynamics, and by combining pressure distributions, several pressure-induced novel physics may be comprehended. In this work, noninvasive, high-resolution two-dimensional images of the current density and pressure gradient for graphene ribbon and hBN-graphene-hBN devices are explored using nitrogen-vacancy (NV) centers in diamond under high pressure. The two-dimensional vector current density is reconstructed by the vector magnetic field mapped by the near-surface NV center layer in the diamond. The current density images accurately and clearly reproduce the complicated structure and current flow of graphene under high pressure. Additionally, the spatial distribution of the pressure is simultaneously mapped, rationalizing the nonuniformity of the current density under high pressure. The current method opens a significant new avenue to investigate electronic transport and conductance variations in two-dimensional materials and electrical devices under high pressure as well as for nondestructive evaluation of semiconductor circuits.

Robust Tensor-Based DOA and Polarization Estimation in Conformal Polarization Sensitive Array with Bad Data.

Partially impaired sensor arrays pose a significant challenge in accurately estimating signal parameters. The occurrence of bad data is highly probable, resulting in random loss of source information and substantial performance degradation in parameter estimation. In this paper, a tensor variational sparse Bayesian learning (TVSBL) method is proposed for the estimate of direction of arrival (DOA) and polarization parameters jointly based on a conformal polarization sensitive array (CPSA), taking into account scenarios with the partially impaired sensor array. First, a sparse tensor-based received data model is developed for CPSAs that incorporates bad data. Then, a column vector detection method is proposed to diagnose the positions of the impaired sensors. In scenarios involving partially impaired sensor arrays, a low-rank matrix completion method is employed to recover the random loss of signal information. Finally, variational sparse Bayesian learning (VSBL) and minimum eigenvector methods are utilized sequentially to obtain the DOA and polarization parameters estimation, successively. Furthermore, the Cramér-Rao bound is given for the proposed method. Simulation results validated the effectiveness of the proposed method.

A Review of Capacity Decay Studies of All-vanadium Redox Flow Batteries: Mechanism and State Estimation.

As a promising large-scale energy storage technology, all-vanadium redox flow battery has garnered considerable attention. However, the issue of capacity decay significantly hinders its further development, and thus the problem remains to be systematically sorted out and further explored. This review provides comprehensive insights into the multiple factors contributing to capacity decay, encompassing vanadium cross-over, self-discharge reactions, water molecules migration, gas evolution reactions, and vanadium precipitation. Subsequently, it analyzes the impact of various battery parameters on capacity. Based on this foundation, the article expounds upon the significance of battery internal state estimation technology. Additionally, the review also summarizes domestic and international mathematical models utilized for simulating capacity decay, serving as a valuable reference for future research endeavors. Finally, through the comparison of traditional experimental methods and mathematical modeling methods, this article offers effective guidance for the future development direction of battery state monitoring. This review generally overview the problems related to the capacity attenuation of all-vanadium flow batteries, which is of great significance for understanding the mechanism behind capacity decay and state monitoring technology of all-vanadium redox flow battery.

Detection of colinear blocks and synteny and evolutionary analyses based on utilization of MCScanX.

As different taxa evolve, gene order often changes slowly enough that chromosomal 'blocks' with conserved gene orders (synteny) are discernible. The MCScanX toolkit ( https://github.com/wyp1125/MCScanX ) was published in 2012 as freely available software for the detection of such 'colinear blocks' and subsequent synteny and evolutionary analyses based on genome-wide gene location and protein sequence information. Owing to its simplicity and high efficiency for colinear block detection, MCScanX provides a powerful tool for conducting diverse synteny and evolutionary analyses. Moreover, the detection of colinear blocks has been embraced as an integral step for pangenome graph construction. Here, new application trends of MCScanX are explored, striving to better connect this increasingly used tool to other tools and accelerate insight generation from exponentially growing sequence data. We provide a detailed protocol that covers how to install MCScanX on diverse platforms, tune parameters, prepare input files from data from the National Center for Biotechnology Information, run MCScanX and its visualization and evolutionary analysis tools, and connect MCScanX with external tools, including MCScanX-transposed, Circos and SynVisio. This protocol is easily implemented by users with minimal computational background and is adaptable to new data of interest to them. The data and utility programs for this protocol can be obtained from http://bdx-consulting.com/mcscanx-protocol .

Exact Solution of the Bose-Hubbard Model with Unidirectional Hopping.

A one-dimensional Bose-Hubbard model with unidirectional hopping is shown to be exactly solvable. Applying the algebraic Bethe ansatz method, we prove the integrability of the model and derive the Bethe ansatz equations. The exact eigenvalue spectrum can be obtained by solving these equations. The distribution of Bethe roots reveals the presence of a superfluid-Mott insulator transition at the ground state, and the critical point is determined. By adjusting the boundary parameter, we demonstrate the existence of a non-Hermitian skin effect even in the presence of interaction, but it is completely suppressed for the Mott insulator state in the thermodynamical limit. Our result represents a new class of exactly solvable non-Hermitian many-body systems, which has no Hermitian correspondence and can be used as a benchmark for various numerical techniques developed for non-Hermitian many-body systems.

Meta-analysis of the influence of tracheal intubation with cuff and without cuff on the incidence of total wound complications in ICU intubation patients.

At present, it is still controversial whether patients in intensive care unit (ICU) use tracheal intubation with or without cuff. This paper evaluates the effect of tracheal intubation with and without cuff on overall complication rate of patients with intubation in ICU. The database of PubMed, Embase, Conchrane Library and Web of Science was searched by computer, and the clinical research on intubation with and without cuff in ICU was collected. The time range was from the database establishment to November 2023. Literature was independently screened, information was extracted, and quality was assessed by two researchers. Finally, there were nine studies included, with 11 068 patients (7391 in cuff group and 3677 in non-cuff group). The results showed that the overall complication rate of cuff group was significantly lower than that of non-cuff group, and that of cuff group (RR = 0.53, p < 0.01). In addition, compared with the non-cuff group, the cuff group had a lower number of tracheal intubation changes [RR = 0.05, p < 0.01] and a lower incidence of aspiration pneumonia (RR = 0.45, p = 0.01). Compared with the non-cuff group, the cuff group had a higher incidence of oral mucosal ulcers and pharyngitis (RR = 1.99, p = 0.04), while the cuff group had a lower incidence of laryngeal edema (RR = 0.39, p < 0.01). In ICU intubation patients, the use of cuffs reduces overall complication rate in comparison to patients without cuffs. Therefore, patients with intubation in ICU can recommend tracheal intubation with cuff.

High-performance cryo-temperature ionic thermoelectric liquid cell developed through a eutectic solvent strategy.

Ionic thermoelectric (i-TE) liquid cells offer an environmentally friendly, cost effective, and easy-operation route to low-grade heat recovery. However, the lowest temperature is limited by the freezing temperature of the aqueous electrolyte. Applying a eutectic solvent strategy, we fabricate a high-performance cryo-temperature i-TE liquid cell. Formamide is used as a chaotic organic solvent that destroys the hydrogen bond network between water molecules, forming a deep eutectic solvent that enables the cell to operate near cryo temperatures (down to -35 °C). After synergistic optimization of the electrode and cell structure, the as-fabricated liquid i-TE cell with cold (-35 °C) and hot (70 °C) ends achieve a high power density (17.5 W m-2) and a large two-hour energy density (27 kJ m-2). In a prototype 25-cell module, the open-circuit voltage and short-circuit current are 6.9 V and 68 mA, respectively, and the maximum power is 131 mW. The anti-freezing ability and high output performance of the as-fabricated i-TE liquid cell system are requisites for applications in frigid regions.

Polaron interfacial entropy as a route to high thermoelectric performance in DAE-doped PEDOT:PSS films.

Enhancing the thermoelectric transport properties of conductive polymer materials has been a long-term challenge, in spite of the success seen with molecular doping strategies. However, the strong coupling between the thermopower and the electrical conductivity limits thermoelectric performance. Here, we use polaron interfacial occupied entropy engineering to break through this intercoupling for a PEDOT:PSS (poly(3,4-ethylenedioxythiophene)-poly(4-styrenesulfonate)) thin film by using photochromic diarylethene (DAE) dopants coupled with UV-light modulation. With a 10-fold enhancement of the thermopower from 13.5 µV K-1 to 135.4 µV K-1 and almost unchanged electrical conductivity, the DAE-doped PEDOT:PSS thin film achieved an extremely high power factor of 521.28 µW m-1 K-2 from an original value of 6.78 µW m-1 K-2. The thermopower was positively correlated with the UV-light intensity but decreased with increasing temperature, indicating resonant coupling between the planar closed DAE molecule and PEDOT. Both the experiments and theoretical calculations consistently confirmed the formation of an interface state due to this resonant coupling. Interfacial entropy engineering of polarons could play a critical role in enhancing the thermoelectric performance of the organic film.

Stress and strain analysis and parameter optimization of pipe truss tower connection of super-large tower crane based on FEM.

Clamping bushing structure is an internode connection mechanism designed for the standard section of tubular truss tower. In this paper, the clamping bushing structure of the connecting mechanism of super-large tower crane is taken as the research object, a three-dimensional model of clamping bushing structure is established and imported into ABAQUS, and its multi-body contact model is further constructed to study the contact and bearing relationship of the structure under multiple working conditions, and the accuracy of the calculation results of the model is verified by the experimental stress test under tensile working conditions. In addition, this study is based on the control variable method, and through the design of orthogonal test table, the influence degree of five variable parameters of clamping bushing on the bearing capacity of the structure is investigated. Finally, through the range analysis, the optimal horizontal combination of variables and parameters of clamping bushing structure is obtained, and the optimal matching relationship between the shape of the tower connecting mechanism and the bearing capacity is obtained. The results show that, compared with the original model, the stress concentration at the most dangerous section of the optimized joint and the bushing is obviously alleviated, in which the stress peaks of the upper and lower joints are kept below 500 MPa, and the stress peaks of the bushing groove are also reduced to between 573 and 722 MPa. Moreover, the designed and optimized lower joint can reduce the maximum equivalent plastic strain of the joint root circumference by 56.05% under the original maximum tensile condition, and the overall distribution trend of equivalent plastic strain is more uniform, and a more reliable structural design is obtained, which plays an important guiding role in the design, optimization and analysis of the connecting mechanism of the tower body of large tower crane.

Genomics insights into flowering and floral pattern formation: regional duplication and seasonal pattern of gene expression in Camellia.

BACKGROUND: The formation and domestication of ornamental traits are influenced by various aspects, such as the recognition of esthetic values and cultural traditions. Camellia japonica is widely appreciated and domesticated around the world mainly due to its rich variations in ornamental traits. Ornamental camellias have a diverse range of resources, including different bud variations from Camellia spp. as well as inter- and intra- specific hybridization. Despite research on the formation of ornamental traits, a basic understanding of their genetics and genomics is still lacking. RESULTS: Here, we report the chromosomal-level reference genome of C. japonica through combining multiple DNA-sequencing technologies and obtain a high-density genetic linkage map of 4255 markers by sequencing 98 interspecific F1 hybrids between C. japonica and C. chekiangoleosa. We identify two whole-genome duplication events in C. japonica: one is a shared ancient γ event, and the other is revealed to be specific to genus Camellia. Based on the micro-collinearity analysis, we find large-scale segmental duplication of chromosome 8, resulting to two copies of the AGAMOUS loci, which may play a key role in the domestication of floral shapes. To explore the regulatory mechanisms of seasonal flowering, we have analyzed year-round gene expression patterns of C. japonica and C. azalea-a sister plant of continuous flowering that has been widely used for cross breeding. Through comparative analyses of gene co-expression networks and annual gene expression patterns, we show that annual expression rhythms of some important regulators of seasonal growth and development, including GIGANTEA and CONSTANS of the photoperiod pathway, have been disrupted in C. azalea. Furthermore, we reveal that the distinctive expression patterns of FLOWERING LOCUS T can be correlated with the seasonal activities of flowering and flushing. We demonstrate that the regulatory module involved in GIGANTEA, CONSTANS, and FLOWERING LOCUS T is central to achieve seasonality. CONCLUSIONS: Through the genomic and comparative genomics characterizations of ornamental Camellia spp., we propose that duplication of chromosomal segments as well as the establishment of gene expression patterns has played a key role in the formation of ornamental traits (e.g., flower shape, flowering time). This work provides a valuable genomic platform for understanding the molecular basis of ornamental traits.

Identification of crucial anoikis-related genes as novel biomarkers and potential therapeutic targets for lung adenocarcinoma via bioinformatic analysis and experimental verification.

Lung adenocarcinoma (LUAD) is a malignant tumor of the respiratory system that has a poor 5-year survival rate. Anoikis, a type of programmed cell death, contributes to tumor development and metastasis. The aim of this study was to develop an anoikis-based stratified model, and a multivariable-based nomogram for guiding clinical therapy for LUAD. Through differentially expressed analysis, univariate Cox, LASSO Cox regression, and random forest algorithm analysis, we established a 4 anoikis-related genes-based stratified model, and a multivariable-based nomogram, which could accurately predict the prognosis of LUAD patients in the TCGA and GEO databases, respectively. The low and high-risk score LUAD patients stratified by the model showed different tumor mutation burden, tumor microenvironment, gemcitabine sensitivity and immune checkpoint expressions. Through immunohistochemical analysis of clinical LUAD samples, we found that the 4 anoikis-related genes (PLK1, SLC2A1, ANGPTL4, CDKN3) were highly expressed in the tumor samples from clinical LUAD patients, and knockdown of these genes in LUAD cells by transfection with small interfering RNAs significantly inhibited LUAD cell proliferation and migration, and promoted anoikis. In conclusion, we developed an anoikis-based stratified model and a multivariable-based nomogram of LUAD, which could predict the survival of LUAD patients and guide clinical treatment.

Using Cu-Based Metal-Organic Framework as a Comprehensive and Powerful Antioxidant Nanozyme for Efficient Osteoarthritis Treatment.

Developing nanozymes with effective reactive oxygen species (ROS) scavenging ability is a promising approach for osteoarthritis (OA) treatment. Nonetheless, numerous nanozymes lie in their relatively low antioxidant activity. In certain circumstances, some of these nanozymes may even instigate ROS production to cause side effects. To address these challenges, a copper-based metal-organic framework (Cu MOF) nanozyme is designed and applied for OA treatment. Cu MOF exhibits comprehensive and powerful activities (i.e., SOD-like, CAT-like, and •OH scavenging activities) while negligible pro-oxidant activities (POD- and OXD-like activities). Collectively, Cu MOF nanozyme is more effective at scavenging various types of ROS than other Cu-based antioxidants, such as commercial CuO and Cu single-atom nanozyme. Density functional theory calculations also confirm the origin of its outstanding enzyme-like activities. In vitro and in vivo results demonstrate that Cu MOF nanozyme exhibits an excellent ability to decrease intracellular ROS levels and relieve hypoxic microenvironment of synovial macrophages. As a result, Cu MOF nanozyme can modulate the polarization of macrophages from pro-inflammatory M1 to anti-inflammatory M2 subtype, and inhibit the degradation of cartilage matrix for efficient OA treatment. The excellent biocompatibility and protective properties of Cu MOF nanozyme make it a valuable asset in treating ROS-related ailments beyond OA.

Hypoxia-Mediated Upregulation of Xanthine Oxidoreductase Causes DNA Damage of Colonic Epithelial Cells in Colitis.

Xanthine oxidoreductase (XOR) serves as the primary source of hydrogen peroxide and superoxide anions in the intestinal mucosa. However, its specific contribution to the progression of colonic disease remains unclear. In this study, we investigated the role of XOR in ulcerative colitis (UC) and attempted to identify the underlying mechanisms. We used the dextran sulfate sodium (DSS)-induced mouse model to mimic UC and observed that XOR inhibitors, allopurinol and diphenyleneiodonium sulfate (DPI), significantly alleviated UC in mice. In addition, treatment with cobalt chloride (CoCl2) and 1% O2 increased the expression of XOR and induced DNA oxidative damage in colonic epithelial cells. Furthermore, we identified that XOR accumulation in the nucleus may directly cause DNA oxidative damage and regulates HIF1α protein levels. In addition, allopurinol effectively protected colon epithelial cells from CoCl2-induced DNA damage. Altogether, our data provided evidence that XOR could induce DNA damage under hypoxic conditions, indicating a significant role of XOR in the initiation and early development of colitis-associated colorectal cancer (CAC).

Autologous Tumor-Infiltrating Lymphocyte Mono-Therapy Can Rapidly Shrank Tumor in Asian Patient with Stage III/IV Cervical Cancer: Two Cases Report.

Introduction: Tumor-infiltrating lymphocytes (TILs) therapy is one of the most promising adoptive T cell therapies, which has shown great clinical efficacy against several solid malignancies. Nevertheless, clinical response to TILs mono-therapy in Asian patients with recurrent cervical cancer has not been well reported. Case Presentation: Here, we report two patients who were diagnosed with metastatic cervical cancer and tumor progression following multiple conventional treatments. In particular, one of the patients has a history of severe myelosuppression after chemotherapy. The patients received lymphodepletion therapy, which consisted of cyclophosphamide (30mg/kg) for 2 days, followed by Fludarabine (25mg/m2) for 5 days, approximately 24 hr before receiving intravenous autologous TILs infusion. These two patients then received high doses of IL-2 for 10 days with the purpose of maintaining T cell survival and proliferation. Patient 1 experienced clinical partial response (PR) at 6 weeks post TILs infusion and a 33% tumor shrinkage at 12 weeks follow-up, and patient 2 was evaluated as stable disease (SD) at 6 weeks post treatment. Mild and manageable adverse events were observed and soon subsided after the TILs treatment. A time-course study examining the peripheral blood cell count and cytokine secretion demonstrated the persistence of infused TILs and long-term immune response. Conclusion: These results suggest that TILs mono-therapy can be a promising treatment strategy for Asian patients with late-stage metastatic cervical cancer even with severe myelosuppression. TILs infusion can induce persistence and a long-term systematic immune response that reversed peripheral CD4+T and CD8+T percentages implying that TILs infusion increased cytotic T cell responses, which is consistent with clinical responses in these patients. Trial registration number: NCT05366478.