Tumor Target Research Articles

Durable local control with hypofractionated radiation therapy for unresectable or metastatic melanoma

Background and purposeAs patients with advanced melanoma live longer in the context of systemic therapy advancements, better strategies for durable control of bulky tumors are needed. In this study, we evaluated if dose-escalated hypofractionated radiation therapy (HFRT) can provide durable local control and improve tumor-associated symptoms in patients with unresectable or bulky metastatic melanoma for whom stereotactic ablative radiotherapy (RT) approaches are not feasible due to tumor size or location. Materials and methodsWe retrospectively reviewed 49 patients with unresectable or bulky metastatic melanoma who were treated to a total of 53 tumor targets with 12–17 fractions HFRT at our institution between 2015–2022. Clinical scenarios included: unresectable, locoregional only disease (26 %); oligometastatic disease (<3 total sites, 17 %); oligoprogressive disease (<3 sites progressing, 17 %); and aggressive palliation (>5 known sites of disease or with at least 3 sites progressing, 40 %). ResultsOf the 53 HFRT targets, 91 % (n = 48) had radiographic evidence of response as defined by either stabilization (6 %, n = 3), decreased size (74 %, n = 39), or decreased FDG avidity (11 %, n = 6). Of the 43 symptomatic patients, 98 % (n = 42) had symptomatic improvement. One −year local control was 79 %, with 2-year progression-free and overall survival of 33 % and 39 % respectively. The most common acute toxicities were radiation dermatitis (16 %, n = 8) or a pain flare (14 %, n = 7). Late toxicities were uncommon and typically grade 1. ConclusionHFRT provides favorable local control and symptomatic relief with limited toxicity in tumors not amenable to surgical resection or stereotactic ablative RT.

Deep learning method for predicting weekly anatomical changes in patients with nasopharyngeal carcinoma during radiotherapy.

Patients may undergo anatomical changes during radiotherapy, leading to an underdosing of the target or overdosing of the organs at risk (OARs). This study developed a deep-learning method to predict the tumor response of patients with nasopharyngeal carcinoma (NPC) during treatment. This method can predict the anatomical changes of a patient. The participants included 230 patients with NPC. The data included planning computed tomography (pCT) and routine cone-beam CT (CBCT) images. The CBCT image quality was improved to the CT level using an advanced method. A long short-term memory network-generative adversarial network (LSTM-GAN) is proposed, which can harness the forecasting ability of LSTM and the generation ability of GAN. Four models were trained to predict the anatomical changes that occurred in weeks 3-6 and named LSTM-GAN-week 3 to LSTM-GAN-week 6. The pCT and CBCT were used as input, and the tumor target volumes (TVs) and OARs were delineated on the predicted and real images (ground truth). Finally, the models were evaluated using contours and dosimetry parameters. The proposed method predicted the anatomical changes, with a dice similarity coefficient above 0.94 and 0.90 for the TVs and surrounding OARs, respectively. The dosimetry parameters were close between the prediction and ground truth. The deviations in the prescription, minimum, and maximum doses of the tumor targets were below 0.5Gy. For serial organs (brain stem and spinal cord), the deviations in the maximum dose were below 0.6Gy. For parallel organs (bilateral parotid glands), the deviations in the mean dose were below 0.8Gy. The proposed method can predict the tumor response to radiotherapy in the future such that adaptation can be scheduled on time. This study provides a proactive mechanism for planning adaptation, which can enable personalized treatment and save clinical time by anticipating and preparing for treatment strategy adjustments.

Reduction Accelerated Adaptive Step‐Size FISTA Based Smooth‐Lasso Regularization for Fluorescence Molecular Tomography Reconstruction

ABSTRACTIn this paper, a reduced accelerated adaptive fast iterative shrinkage threshold algorithm based on Smooth‐Lasso regularization (SL‐RAFISTA‐BB) is proposed for fluorescence molecular tomography (FMT) 3D reconstruction. This method uses the Smooth‐Lasso regularization to fuse the group sparse prior information which can balance the relationship between the sparsity and smoothness of the solution, simplifying the process of calculation. In particular, the convergence speed of the FISTA is improved by introducing a reduction strategy and Barzilai‐Borwein variable step size factor, and constructing a continuation strategy to reduce computing costs and the number of iterations. The experimental results show that the proposed algorithm not only accelerates the convergence speed of the iterative algorithm, but also improves the positioning accuracy of the tumor target, alleviates the over‐sparse or over‐smooth phenomenon of the reconstructed target, and clearly outlines the boundary information of the tumor target. We hope that this method can promote the development of optical molecular tomography.

Hybrid Liposome-MSN System with Co-Delivering Potential Effective Against Multidrug-Resistant Tumor Targets in Mice Model.

RNA interference (RNAi) stands as a widely employed gene interference technology, with small interfering RNA (siRNA) emerging as a promising tool for cancer treatment. However, the inherent limitations of siRNA, such as easy degradation and low bioavailability, hamper its efficacy in cancer therapy. To address these challenges, this study focused on the development of a nanocarrier system (HLM-N@DOX/R) capable of delivering both siRNA and doxorubicin for the treatment of breast cancer. The study involved a comprehensive investigation into various characteristics of the nanocarrier, including shape, diameter, Fourier transform infrared (FT-IR) spectroscopy, X-ray photoelectron spectroscopy (XPS), encapsulation efficiency, and drug loading. Subsequently, in vitro and in vivo studies were conducted on cytotoxicity, cellular uptake, cellular immunofluorescence, lysosome escape, and mouse tumor models to evaluate the efficacy of the nanocarrier in reversing tumor multidrug resistance and anti-tumor effects. The results showed that HLM-N@DOX/R had a high encapsulation efficiency and drug loading capacity, and exhibited pH/redox dual responsive drug release characteristics. In vitro and in vivo studies showed that HLM-N@DOX/R inhibited the expression of P-gp by 80%, inhibited MDR tumor growth by 71% and eliminated P protein mediated multidrug resistance. In summary, HLM-N holds tremendous potential as an effective and targeted co-delivery system for DOX and P-gp siRNA, offering a promising strategy for overcoming MDR in breast cancer.

Virtual Needle Insertion with Enhanced Haptic Feedback for Guidance and Needle-Tissue Interaction Forces.

Interventional radiologists mainly rely on visual feedback via imaging modalities to steer a needle toward a tumor during biopsy and ablation procedures. In the case of CT-guided procedures, there is a risk of exposure to hazardous X-ray-based ionizing radiation. Therefore, CT scans are usually not used continuously, which increases the chances of a misplacement of the needle and the need for reinsertion, leading to more tissue trauma. Interventionalists also encounter haptic feedback via needle-tissue interaction forces while steering a needle. These forces are useful but insufficient to clearly perceive and identify deep-tissue structures such as tumors. The objective of this paper was to investigate the effect of enhanced force feedback for sensing interaction forces and guiding the needle when applied individually and simultaneously during a virtual CT-guided needle insertion task. We also compared the enhanced haptic feedback to enhanced visual feedback. We hypothesized that enhancing the haptic feedback limits the time needed to reach the target accurately and reduces the number of CT scans, as the interventionalist depends more on real-time enhanced haptic feedback. To test the hypothesis, a simulation environment was developed to virtually steer a needle in five degrees of freedom (DoF) to reach a tumor target embedded in a liver model. Twelve participants performed in the experiment with different feedback conditions where we measured their performance in terms of the following: targeting accuracy, trajectory tracking, number of CT scans required, and the time needed to finish the task. The results suggest that the combination of enhanced haptic feedback for guidance and sensing needle-tissue interaction forces significantly reduce the number of scans and the duration required to finish the task by 32.1% and 46.9%, respectively, when compared to nonenhanced haptic feedback. The other feedback modalities significantly reduced the duration to finish the task by around 30% compared to nonenhanced haptic feedback.

TEAM: Triangular-mEsh Adaptive and Multiscale proton spot generation method.

Proton therapy is preferred for its dose conformality to spare normal tissues and organs-at-risk (OAR) via Bragg peaks with negligible exit dose. However, proton dose conformality can be further optimized: (1) the spot placement is based on the structured (e.g., Cartesian) grid, which may not offer conformal shaping to complex tumor targets; (2) the spot sampling pattern is uniform, which may be insufficient at the tumor boundary to provide the sharp dose falloff, and at the same time may be redundant at the tumor interior to provide the uniform dose coverage, for example, due to multiple Coulomb scattering (MCS); and (3) the lateral spot penumbra increases with respect to the depth due to MCS, which blurs the lateral dose falloff. On the other hand, while (1) the deliverable spots are subject to the minimum-monitor-unit (MMU) constraint, and (2) the dose rate is proportional to the MMU threshold, the current spot sampling method is sensitive to the MMU threshold and can fail to provide satisfactory plan quality for a large MMU threshold (i.e., high-dose-rate delivery). This work will develop a novel Triangular-mEsh-based Adaptive and Multiscale (TEAM) proton spot generation method to address these issues for optimizing proton dose conformality and plan delivery efficiency. Compared to the standard clinically-used spot placement method, three key elements of TEAM are as follows: (1) a triangular mesh instead of a structured grid: the triangular mesh is geometrically more conformal to complex target shapes and therefore more efficient and accurate for dose shaping inside and around the target; (2) adaptive sampling instead of uniform sampling: the adaptive sampling consists of relatively dense sampling at the tumor boundary to create the sharp dose falloff, which is more accurate, and coarse sampling at the tumor interior to uniformly cover the target, which is more efficient; and (3) depth-dependent sampling instead of depth-independent sampling: the depth-dependent sampling is used to compensate for MCS, that is, with increasingly dense sampling at the tumor boundary to improve dose shaping accuracy, and increasingly coarse sampling at the tumor interior to improve dose shaping efficiency, as the depth increases. In the TEAM method the spot locations are generated for each energy layer and layer-by-layer in the multiscale fashion; and then the spot weights are derived by solving the IMPT problem of dose-volume planning objectives, MMU constraints, and robustness optimization with respect to range and setup uncertainties. Compared to the standard clinically-used spot placement method UNIFORM, TEAM achieved (1) better plan quality using <60% number of spots of UNIFORM; (2) better robustness to the number of spots; (3) better robustness to a large MMU threshold. Furthermore, TEAM provided better plan quality with fewer spots than other adaptive methods (Cartesian-grid or triangular-mesh). A novel triangular-mesh-based proton spot placement method called TEAM is proposed, and it is demonstrated to improve plan quality, robustness to the number of spots, and robustness to the MMU threshold, compared to the clinically-used spot placement method and other adaptive methods.

Clinical Factors Influencing the Radiation Dose of Circulating Immune Cells during Radiotherapy for Small Cell Lung Cancer.

Small cell lung cancer (SCLC) has garnered significant attention due to its high malignancy, propensity for distant metastasis, and poor prognosis. Radiotherapy remains the cornerstone of treatment for limited-stage small cell lung cancer (LS-SCLC). However, outcomes with radiotherapy alone or in combination with chemotherapy remain suboptimal. Radiotherapy can induce lymphopenia by directly irradiating hematopoietic organs or destroying mature circulating lymphocytes, leading to immunosuppression and consequently diminishing therapeutic efficacy. The estimated dose of radiation to immune cells (EDRIC) model integrates factors such as hemodynamics, lymphocyte radiosensitivity, and proliferation capacity. This study employs the EDRIC model with enhancements to calculate the circulating immune cell radiation dose. By utilizing the EDRIC methodology, the study explores the correlation between EDRIC and tumor target size, average lung dose, average heart dose, clinical features, and peripheral blood lymphocytopenia during radiotherapy for LS-SCLC, aiming to inform personalized patient treatment strategies. This study analyzed data from 64 LS-SCLC patients who met the inclusion criteria at the General Hospital of Ningxia Medical University from January 2023 to January 2024, all of whom received radical thoracic conventional fractionated radiotherapy. Lymphocyte counts were recorded at the following points: before radiotherapy, at the lowest observed value during radiotherapy, at the end of radiotherapy, and one-month post-radiotherapy. Dosimetric data, including average lung, heart, and body doses, were extracted from the treatment planning system, and the circulating EDRIC was calculated using this model. The relationship between EDRIC values and therapeutic outcomes was analyzed. In LS-SCLC, the EDRIC model effectively predicts lymphocyte count reduction, correlating with planning target volume (PTV; cm3), TNM stage, and the percentage of target lesion shrinkage. Post-radiotherapy, there was a significant decrease in peripheral blood lymphocyte counts, with greater EDRIC values indicating more pronounced lymphocyte reduction.

19 Phase II Trial of Ubamatamab in MUC16-Expressing SMARCB1-Deficient Renal Medullary Carcinoma and Epithelioid Sarcoma

Abstract Background Mucin 16 (MUC16) is a large integral membrane glycoprotein that is highly expressed in malignancies such as ovarian cancer but only at low abundance in epithelial cells of normal tissues. Proteolytic cleavage of cell surface MUC16 results in the shedding of its extracellular portion, known as cancer antigen 125 (CA-125), into the bloodstream and a short, membrane-associated C-terminal MUC16 domain that remains on the cell surface. Renal medullary carcinoma (RMC) and epithelioid sarcoma (ES) are aggressive SMARCB1-deficient malignancies found to have elevated serum CA-125 levels in 70-80% of cases. Our preclinical studies suggest that upregulation of MUC16 upon SMARCB1 loss is a viable and attractive tumor target for SMARCB1-deficient malignancies such as ES and RMC. Ubamatamab is a human IgG4-based anti-MUC16 x anti-CD3 bispecific antibody that specifically targets the cell surface bound C-terminal MUC16 domain and can thus induce T cell–redirected killing of tumor cells even in the presence of high concentrations of CA-125. It would thus be a rationale therapy to use in SMARCB1-deficient malignancies expressing MUC16, including those such as RMC known to downregulate MHC Class I as a resistance mechanism to conventional immunotherapy. This is because CD3-targeting bispecific antibodies such as ubamatamab replace conventional signal 1 by engaging T cells regardless of MHC class I expression. As proof of concept, a 20-year-old patient with metastatic SMARCB1-negative ES expressing high levels of serum CA-125 achieved a durable (12+ months) partial response to ubamatamab after progressing on multiple prior therapies, including EZH2 inhibition with tazemetostat as well as anti-PD1/CTLA4 immune checkpoint inhibition with nivolumab plus ipilimumab. The patient reported Grade 2 CRS, pleural effusion, and pericardial effusion, all of which resolved without intervention1. This serves as proof-of-concept for the ability of CD3-targeted bispecifics to overcome resistance to immune checkpoint inhibition. Given this strong preclinical and clinical evidence, we have developed a phase II clinical trial of ubamatamab alone or in combination with the anti-PD1 immune-checkpoint inhibitor cemiplimab in patients with MUC16-expressing RMC and ES who have progressed on at least one line of prior therapy. Up to 20 patients will be enrolled from each disease cohort (ES and RMC) for a total of up to 40 patients. Patients enrolled in Stage I of the trial will receive ubamatamab monotherapy. Patients with disease progression on ubamatamab monotherapy during Stage I can proceed to stage II, which will evaluate the combination of ubamatamab with cemiplimab combination. The co-primary endpoints will be objective response rate (ORR) at any time during the trial and disease control rate (DCR) through 18 weeks. Secondary endpoints will include overall survival, progression-free survival, duration of response, and safety. All endpoints will be analyzed and reported separately for each disease cohort (RMC and ES), and for each Stage (ubamatamab monotherapy and combination ubamatamab with cemiplimab). The trial will utilize the time-to-event Bayesian Optimal Phase II (TOP) design, which maximizes statistical power with well-controlled type I errors. For patients with ES, the joint null hypotheses are that the objective response rate (ORR) is 15% and the disease control rate (DCR) is 26%. The regimen will be promising if either ORR is greater than 15% or DCR is greater than 26% with 69.6% power to declare this an interesting regimen if ORR is 30% and the DCR is 43%. For patients with RMC, the joint null hypotheses are that the objective response rate (ORR) is 15% and the disease control rate (DCR) is 15%. The regimen will be promising if either ORR is greater than 15% or DCR is greater than 15% with 71.4% power to declare this an interesting regimen if ORR is 30% and the DCR is 30%. Pre- and post-treatment correlative analyses will be performed in blood and tumor biopsy tissues to identify changes in specific immune cell subsets and elucidate the dynamic evolution of tumor and immune cell compartments as well as their spatial relationships following ubamatamab alone or in combination with cemiplimab. References 1 Revon-Riviere G, Chami R, Mills D, et al. Mucin 16 (cancer antigen 125) Expression in Epithelioid Sarcoma leads to Single-Patient Study with Bispecific T-Cell Engager Ubamatamab (Mucin16xCD3): A Bench-To-Bedside Experience. Connective Tissue Oncology Society, Nov 16–19, 2022, Vancouver, Canada.

CD38-CAR human NK cells in combination with ATRA enhance cytotoxicity against CD38-expressing hematologic malignancies

AbstractCD38 is a metabolically active enzyme broadly expressed on the surface of normal and malignant hematologic cells. It has been targeted clinically with anti-CD38 monoclonal antibodies (mAbs), for which efficacy may be limited by natural killer (NK)–cell fratricide. Isatuximab is an anti-CD38 mAb that uniquely inhibits CD38 metabolic activity. Here, we used CRISPR/adeno-associated virus (AAV) to generate fratricide–resistant and metabolically–enhanced CD38KO/CD38-chimeric antigen receptor (CAR) NK cells using 2 isatuximab-based CD38 single-chain variable fragments (scFvs; reversing heavy and light chain orientation) on the same CD8α/4-1BB/CD3ζ base, and we demonstrate their activity against a range of CD38+ hematologic malignancies (acute myeloid leukemia, multiple myeloma, Burkitt lymphoma, and T-cell leukemia/lymphoma). The cytotoxicity of the CAR NK cells was enhanced by upregulating CD38 expression on the malignant targets with all-trans retinoic acid (ATRA). By generating CD38KO/CD38-CAR T cells using the same engineering approach, we show that the CAR NK cells had higher cytotoxicity than CAR T cells against all hematologic tumor targets. Additionally, AAVS1KO/CD38-CAR NK cells were capable of targeting CD38 without experiencing fratricide and have a similar enhanced metabolic activity via the inhibitory activity of the cis-acting isatuximab-based scFv. Finally, we report fratricide-resistant CD38-CAR NK cells with enhanced metabolism and cytotoxicity toward CD38+ hematologic malignancies, further increased by combination treatment with ATRA.

Copper Single-Atom-Based Metal-Organic Framework for Ultrasound-Enhanced Nanocatalytic Therapy.

Chemodynamic therapy (CDT) is an emerging therapeutic modality triggered by endogenous substances in the tumor microenvironment (TME) to generate reactive oxygen species. However, the mild acid pH, low H2O2 concentration, and overexpressed glutathione can suppress the CDT efficiency. Herein, ultrasound (US)-triggered Cu2+-based single-atom nanoenzymes (FA-NH2-UiO-66-Cu, FNUC) are constructed with the performance of target and glutathione depletion. In the TME, the single-atom Cu sites of FNUC consume glutathione and the FNUC:Cu+ generates •OH via peroxidase-like activity. The US-activated FNUC exhibits a fast •OH generation rate, a low Michaelis constant, and a large •OH concentration, indicating the cavitation effect of US promotes the •OH generation. Meanwhile, the tumor target of FNUC is confirmed by NIR-II fluorescence imaging, in which it is modified with IR-1061. Combined with the antitumor performance of FNUC in vitro and in vivo, the novel Cu-based SAzymes can achieve efficient and precise cancer treatment.

L-proline H2SO4 catalyzed synthesis of novel coumarin-based spiroindolino-3,4-dihydropyrimidin-2(1H)-ones: in vitro cytotoxic assay and molecular docking study.

Development of environmentally benign catalyst systems, especially those derived from readily available nature's pool, in multicomponent synthesis, consolidates multiple facets of green chemistry. Here, an L-proline derived green acid catalyst in the form of L-proline⋅H2SO4 was developed and employed for multicomponent synthesis of coumarin-based spiroindolino-3,4-dihydropyrimidin-2(1H)-ones from the reaction of 4-hydroxycoumarin, isatin and urea/thiourea. Preliminary cytotoxicity studies showed that a couple of compounds (M5 and M6) have good cytotoxicity (40-50%) against in Dalton's Lymphoma (DL) cells while demonstrating minimal cytotoxicity (10-12%) for normal non-cancerous cell lines. Molecular docking simulations for the least and most cytotoxic compounds, M3 and M6 respectively, against nineteen tumor target proteins were carried out, and seven of them were identified to test against all the sixteen compounds. Based on the estimated docking score and inhibition constants (Ki), the interaction of the compounds with the tumor target protein, beta-hexosaminidase B (PDB ID: 1NOW) matched closely with in vitro cytotoxicity data.

Mutagenicity evaluation of methyl tertiary- butyl ether in multiple tissues of transgenic rats following whole body inhalation exposure.

Methyl tertiary-butyl ether (MTBE) is used as a component of motor vehicle fuel to enhance combustion efficiency and to reduce emissions of carbon monoxide and nitrogen oxides. Although MTBE was largely negative in the in vitro and in vivo genotoxicity studies, isolated reports of positive findings along with the observation of tumors in the rat cancer bioassays raised concern for its in vivo mutagenic potential. To investigate this, transgenic male Big Blue Fischer 344 rats were exposed to 0 (negative control), 400, 1000, and 3000 ppm MTBE via whole body inhalation for 28 consecutive days, 6 h/day. Mutant frequencies (MF) at the cII locus of the transgene in the nasal epithelium (portal of entry tissue), liver (site of primary metabolism), bone marrow (rapidly proliferating tissue), and kidney (tumor target) were analyzed (5 rats/exposure group) following a 3-day post-exposure manifestation period. MTBE did not induce a mutagenic response in any of the tissues investigated. The adequacy of the experimental conditions to detect induced mutations was confirmed by utilizing tissue samples from animals treated with the known mutagen ethyl nitrosourea. These data provide support to the conclusion that MTBE is not an in vivo mutagen and male rat kidney tumors are not likely the result of a mutagenic mode of action.

Applications of Modified Mesenchymal Stem Cells as Targeted Systems against Tumor Cells.

Combined gene and cell therapy are promising strategies for cancer treatment. Given the complexity of cancer, several approaches are actively studied to fight this disease. Using mesenchymal stem cells (MSCs) has demonstrated dual antitumor and protumor effects as they exert massive immune/regulatory effects on the tissue microenvironment. MSCs have been widely investigated to exploit their antitumor target delivery system. They can be genetically modified to overexpress genes and selectively or more efficiently eliminate tumor cells. Current approaches tend to produce more effective and safer therapies using MSCs or derivatives; however, the effect achieved by engineered MSCs in solid tumors is still limited and depends on several factors such as the cell source, transgene, and tumor target. This review describes the progress of gene and cell therapy focused on MSCs as a cornerstone against solid tumors, addressing the different MSC-engineering methods that have been approached over decades of research. Furthermore, we summarize the main objectives of engineered MSCs against the most common cancers and discuss the challenges, limitations, risks, and advantages of targeted treatments combined with conventional ones.

MR–CT image fusion method of intracranial tumors based on Res2Net

BackgroundInformation complementarity can be achieved by fusing MR and CT images, and fusion images have abundant soft tissue and bone information, facilitating accurate auxiliary diagnosis and tumor target delineation.PurposeThe purpose of this study was to construct high-quality fusion images based on the MR and CT images of intracranial tumors by using the Residual-Residual Network (Res2Net) method.MethodsThis paper proposes an MR and CT image fusion method based on Res2Net. The method comprises three components: feature extractor, fusion layer, and reconstructor. The feature extractor utilizes the Res2Net framework to extract multiscale features from source images. The fusion layer incorporates a fusion strategy based on spatial mean attention, adaptively adjusting fusion weights for feature maps at each position to preserve fine details from the source images. Finally, fused features are input into the feature reconstructor to reconstruct a fused image.ResultsQualitative results indicate that the proposed fusion method exhibits clear boundary contours and accurate localization of tumor regions. Quantitative results show that the method achieves average gradient, spatial frequency, entropy, and visual information fidelity for fusion metrics of 4.6771, 13.2055, 1.8663, and 0.5176, respectively. Comprehensive experimental results demonstrate that the proposed method preserves more texture details and structural information in fused images than advanced fusion algorithms, reducing spectral artifacts and information loss and performing better in terms of visual quality and objective metrics.ConclusionThe proposed method effectively combines MR and CT image information, allowing the precise localization of tumor region boundaries, assisting clinicians in clinical diagnosis.

Boosting the anti-tumor activity of natural killer cells by caripe 8 – A Carapichea ipecacuanha isolated cyclotide

Cyclotides are head-to-tail cyclized peptides with a unique cystine-knot motif. Their structure provides exceptional resistance against enzymatic, chemical, or thermal degradation compared to other peptides. Peptide-based therapeutics promise high specificity, selectivity and lower immunogenicity, making them safer alternatives to small molecules or large biologicals. Cyclotides were researched due to their anti-cancer properties by inducing apoptosis in tumor cells in the past, but the impact of cyclotides on cytotoxic immune cells was poorly studied. Natural Killer (NK) cells are cytotoxic innate lymphoid cells and play an important role in the defense against infected, stressed and transformed cells. NK cells do not need prior sensitization and act in an antigen independent manner, holding promising potential in the field of immunotherapy. To investigate the effect of immunomodulatory cyclotides on NK cells, we evaluated several peptide-enriched plant extracts on NK cell mediated cytotoxicity. We observed that the extract samples derived from Carapichea ipecacuanha (Brot.) L. Andersson augments the killing potential of mouse NK cells against different tumor targets in vitro. Subsequent isolation of cyclotides from C. ipecacuanha extracts led to the identification of a primary candidate that enhances cytotoxicity of both mouse and human NK cells. The augmented killing is facilitated by the increased degranulation capacity of NK cells. In addition, we noted a direct toxic effect of caripe 8 on tumor cells, suggesting a dual therapeutic potential in cancer treatment. This study offers novel insights how natural peptides can influence NK cell cytotoxicity. These pre-clinical findings hold significant promise for advancing current immunotherapeutic approaches.

Autonomous Trajectory Planning for Ultrasound-Guided Real-Time Tracking of Suspicious Breast Tumor Targets

Ultrasound image guidance could display the movement of soft tissue in real time, which provides an important basis for the operation path selection of tumor for examinations and interventions such as precise localization and puncture biopsy. However, factors such as tissue deformation, patient motion, and instrument contact pose great challenges for real-time smooth localization tracking of target tissues and maintaining a suitable acoustic window. Not only does it reduce the accuracy of ultrasound examination, but also may prolong the examination time. In this paper, a real-time autonomous ultrasound robot trajectory planning framework is proposed to achieve global scanning of breast tissue and real-time local tracking of suspicious tumor targets. In addition, an ultrasound suspicious tumor target next moment motion attitude and position estimation algorithm and an acceleration-continuous online trajectory generation (ACOTG) algorithm are proposed. Experiments on breast phantom showed that the fluctuation difference of both global scanning and tracking scanning force was less than 5 N <inline-formula xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink"> <tex-math notation="LaTeX">$\pm$</tex-math> </inline-formula> 15%, and ACOTG takes less than 1 microsecond to calculate the next moment state. The position, velocity, and acceleration of the tracking path did not change abruptly when the unknown target changed. The ultrasound image of the suspected tumor target could always be smoothly maintained in a suitable acoustic window, while the errors between the center of the suspected tumor target image and the center of the acoustic window in the horizontal direction and the depth direction were less than <inline-formula xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink"> <tex-math notation="LaTeX">$\pm$</tex-math> </inline-formula> 1 mm and 30 mm <inline-formula xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink"> <tex-math notation="LaTeX">$\pm$</tex-math> </inline-formula> 10%, respectively. <italic xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">Note to Practitioners</i> —The motivation of this study was to solve the clinical problem of difficulty in keeping the suspected breast tumor target stably in the center of the field of view under the influence of tissue deformation, patient motion and instrument contact in ultrasound guidance. We proposed the idea of global conventional scanning and local online tracking to achieve the autonomous scanning, detecting and tracking of suspicious tumor targets within the global scope of the breast. ACOTG algorithm is proposed and implemented, which can make the ultrasound image of suspicious tumor target can be displayed stably in the center of the acoustic window. With the help of this system, the accuracy of ultrasound examination can be improved and the time of examination can be reduced. The proposed system can also be applied to ultrasound scanning of other parts of the body.

Cross-Domain Feature Disentanglement for Interpretable Modeling of Tumor Microenvironment Impact on Drug Response.

High-throughput screening technology has enabled the generation of large-scale drug responses across hundreds of cancer cell lines. There remains a significant gap between in vitro cell lines and actual tumors in vivo in terms of their response to drug treatments yet. This is because tumors consist of a complex cellular composition and histopathology structure, known as the tumor microenvironment (TME), which greatly impacts the drug cytotoxicity against tumor cells. To date, no study has focused on modeling the impact of the TME on clinical drug response. In this study, we postulated that the intricate complexity of an actual tumor can be conceptually simplified into two separable components: cancerous cells and the tumor microenvironment. This assumption allowed us to model the influence of these two constituent parts on drug response through feature disentanglement. We employed a domain adaptation network to decouple and extract features from tumor transcriptional profiles. Specifically, two denoising autoencoders were separately used to extract features from cell lines (source domain) and tumors (target domain) for partial domain alignment and feature decoupling. The private encoder was enforced to extract information only about the TME. Moreover, to ensure generalizability to novel drugs, we employed a graph attention network to learn the latent representation of drugs, enabling us to linearly model the drug perturbation on cellular state in latent space. We validated our model on a benchmark dataset and demonstrated its superior performance in predicting clinical drug response and dissecting the influence of the TME on drug efficacy.

A Flow Cytometry-Based Method for Assessing CAR Cell Binding Kinetics Using Stable CAR Jurkat Cells.

Chimeric antigen receptors (CARs) are synthetic fusion proteins that can reprogram immune cells to target specific antigens. CAR-expressing T cells have emerged as an effective treatment method for hematological cancers; despite this success, the mechanisms and structural properties that govern CAR responses are not fully understood. Here, we provide a simple assay to assess cellular avidity using a standard flow cytometer. This assay measures the interaction kinetics of CAR-expressing T cells and targets antigen-expressing target cells. By co-culturing stably transfected CAR Jurkat cells with target positive and negative cells for short periods of time in a varying effector-target gradient, we were able to observe the formation of CAR-target cell doublets, providing a readout of actively bound cells. When using the optimized protocol reported here, we observed unique cellular binding curves that varied between CAR constructs with differing antigen binding domains. The cellular binding kinetics of unique CARs remained consistent, were dependent on specific target antigen expression, and required active biological signaling. While existing literature is not clear at this time whether higher or lower CAR cell binding is beneficial to CAR therapeutic activity, the application of this simplified protocol for assessing CAR binding could lead to a better understanding of the proximal signaling events that regulate CAR functionality. Key features • Determines CAR receptor cellular interaction kinetics using a Jurkat cell model. • Can be used for a wide variety of CAR target antigens, including both hematological and solid tumor targets. • Experiments can be performed in under two hours with no staining using a standard flow cytometer. • Requires stable CAR Jurkat cells and target cells with stable fluorescent marker expression for optimal results.

Drug Delivery Opportunities in Esophageal Cancer: Current Treatments and Future Prospects.

With one of the highest mortality rates of all malignancies, the 5-year survival rate for esophageal cancer is under 20%. Depending on the stage and extent of the disease, the current standard of care treatment paradigm includes chemotherapy or chemoradiotherapy followed by surgical esophagogastrectomy, with consideration for adjuvant immunotherapy for residual disease. This regimen has high morbidity, due to anatomic changes inherent in surgery, the acuity of surgical complications, and off-target effects of systemic chemotherapy and immunotherapy. We begin with a review of current treatments, then discuss new and emerging targets for therapies and advanced drug delivery systems. Recent and ongoing preclinical and early clinical studies are evaluating traditional tumor targets (e.g., human epidermal growth factor receptor 2), as well as promising new targets such as Yes-associated protein 1 or mammalian target of rapamycin to develop new treatments for this disease. Due the function and location of the esophagus, opportunities also exist to pair these treatments with a drug delivery strategy to increase tumor targeting, bioavailability, and intratumor concentrations, with the two most common delivery platforms being stents and nanoparticles. Finally, early results with antibody drug conjugates and chimeric antigenic receptor T cells show promise as upcoming therapies. This review discusses these innovations in therapeutics and drug delivery in the context of their successes and failures, with the goal of identifying those solutions that demonstrate the most promise to shift the paradigm in treating this deadly disease.

ATP citrate lyase promotes the progression of hepatocellular carcinoma by activating the REGγ-proteasome pathway.

The search for novel tumor biomarkers and targets is of significant importance for the early clinical diagnosis and treatment of Hepatocellular Carcinoma (HCC). The mechanisms by which ATP citrate lyase (ACLY) promotes HCC progression remain unclear, and the connection between ACLY and REGγ has not been reported in the literature. In vitro, we will perform overexpression/knockdown of ACLY or overexpression/knockdown of REGγ to investigate the impact of ACLY on HCC cells and its underlying mechanisms. In vivo, we will establish mouse tumor models with overexpression/knockdown of ACLY or overexpression/knockdown of REGγ to study the effect of ACLY on mouse tumors and its mechanisms. Firstly, ACLY overexpression upregulated REGγ expression and activated the REGγ-proteasome pathway, leading to changes in the expression of downstream signaling pathway proteins. This promoted HCC cell proliferation, invasion, and migration in vitro, as well as tumor growth and metastasis in vivo. Secondly, ACLY overexpression increased acetyl-CoA production, upregulated the acetylation level of the REGγ promoter region histone H3K27ac, and subsequently induced REGγ expression. Lastly, enhanced acetylation of the REGγ promoter region histone H3K27ac resulted in upregulated REGγ expression, activation of the REGγ-proteasome pathway, changes in downstream signaling pathway protein expression, and promotion of HCC cell proliferation, invasion, and migration in vitro, as well as tumor growth and metastasis in vivo. Conversely, REGγ knockdown reversed these effects. ACLY and REGγ may serve as potential biomarkers and clinical therapeutic targets for HCC.