Single Target Research Articles

Multivalent Aptamer-Based Lysosome-Targeting Chimeras (LYTACs) Platform for Mono- or Dual-Targeted Proteins Degradation on Cell Surface.

Selective protein degradation platforms have opened novel avenues in therapeutic development and biological inquiry. Antibody-based lysosome-targeting chimeras (LYTACs) have emerged as a promising technology that extends the scope of targeted protein degradation to extracellular targets. Aptamers offer an advantageous alternative owing to their potential for modification and manipulation toward a multivalent state. In this study, a chemically engineered platform of multivalent aptamer-based LYTACs (AptLYTACs) is established for the targeted degradation of either single or dual protein targets. Leveraging the biotin-streptavidin system as a molecular scaffold, this investigation reveals that trivalently mono-targeted AptLYTACs demonstrate optimum efficiency in degrading membrane proteins. The development of this multivalent AptLYTACs platform provides a principle of concept for mono-/dual-targets degradation, expanding the possibilities of targeted protein degradation.

An isotope dilution-liquid chromatography-tandem mass spectrometry (ID-LC-MS/MS)-based candidate reference measurement procedure (RMP) for the quantification of phenobarbital in human serum and plasma.

Phenobarbital serves as an antiepileptic drug (AED) and finds application in the treatment of epilepsy either as monotherapy or adjunctive therapy. This drug exhibits various pharmacodynamic properties that account for its beneficial effects as well as potential side effects. Accurate measurement of its concentration is critical for optimizing AED therapy through appropriate dose adjustments. Therefore, our objective was to develop and validate a new reference measurement procedure (RMP) for the accurate quantification of phenobarbital levels in human serum and plasma. A sample preparation protocol based on protein precipitation followed by a high dilution step was established in combination with a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method using a C8 column to separate target analytes from known and unknown interferences. Assay validation and determination of measurement uncertainty were performed based on current guidelines. Selectivity and Specificity were assessed using spiked serum and plasma samples; to investigate possible matrix effects (MEs) a post-column infusion experiment and a comparison of standard line slopes was performed. Precision and accuracy were determined within a multiday precision experiment. The RMP was shown to be highly selective and specific, with no evidence of matrix interferences. It can be used to quantify phenobarbital in the range of 1.92 to 72.0 μg/mL. Intermediate precision was less than 3.2 %, and repeatability coefficient of variation (CV) ranged from 1.3 to 2.0 % across all concentration levels. The relative mean bias ranged from -3.0 to -0.7 % for native serum levels, and from -2.8 to 0.8 % for Li-heparin plasma levels. The measurement uncertainties (k=1) for single measurements and target value assignment were 1.9 to 3.3 % and 0.9 to 1.6 %, respectively. A novel LC-MS/MS-based candidate RMP for the quantification of phenobarbital in human serum and plasma is presented which can be used for the standardization of routine assays and the evaluation of clinically relevant samples.

DERNA Enables Pareto Optimal RNA Design.

The design of an RNA sequence that encodes an input target protein sequence is a crucial aspect of messenger RNA (mRNA) vaccine development. There are an exponential number of possible RNA sequences for a single target protein due to codon degeneracy. These potential RNA sequences can assume various secondary structure conformations, each with distinct minimum free energy (MFE), impacting thermodynamic stability and mRNA half-life. Furthermore, the presence of species-specific codon usage bias, quantified by the codon adaptation index (CAI), plays a vital role in translation efficiency. While earlier studies focused on optimizing either MFE or CAI, recent research has underscored the advantages of simultaneously optimizing both objectives. However, optimizing one objective comes at the expense of the other. In this work, we present the Pareto Optimal RNA Design problem, aiming to identify the set of Pareto optimal solutions for which no alternative solutions exist that exhibit better MFE and CAI values. Our algorithm DEsign RNA (DERNA) uses the weighted sum method to enumerate the Pareto front by optimizing convex combinations of both objectives. We use dynamic programming to solve each convex combination in time and space. Compared with a CDSfold, previous approach that only optimizes MFE, we show on a benchmark data set that DERNA obtains solutions with identical MFE but superior CAI. Moreover, we show that DERNA matches the performance in terms of solution quality of LinearDesign, a recent approach that similarly seeks to balance MFE and CAI. We conclude by demonstrating our method's potential for mRNA vaccine design for the SARS-CoV-2 spike protein.

A real-time patient-specific treatment strategy for enhanced external counterpulsation.

Diastolic/systolic blood pressure ratio (D/S) ≥ 1.2 is the gold standard of enhanced external counterpulsation (EECP) treatment, but it does not show a clear clinical correspondence with the configuration of the EECP mode. As such, a single target results in different treatment effects in different individuals. The local haemodynamic effect (wall shear stress, WSS) of EECP on vascular endothelial cells is conducive to promote the growth of collateral circulation vessels and restore the blood supply distal to the stenosis lesion. Considering the haemodynamic effects of WSS on human arteries, this study developed a real-time patient-specific treatment strategy of EECP for patients with cardio-cerebrovascular diseases. Based on patient-specific haemodynamic data from 113 individuals, an optimization algorithm was developed to achieve the individualization of a 0D lumped-parameter model of the human circulatory system, thereby simulating the patient-specific global haemodynamic effects. 0D/3D coupled cardio-cerebrovascular models of two subjects were established to simulate the local WSS. We then established statistical models to evaluate clinically unmeasurable WSS based on measurable global haemodynamic indicators. With the aim of attaining appropriate area- and time-averaged WSS (ATAWSS, 4-7 Pa), as evaluated by global haemodynamic indicators, a closed-loop feedback tuning method was developed to provide patient-specific EECP treatment strategies. Results showed that for clinical data collected from 113 individuals, the individualized 0D model can accurately simulate patient-specific global haemodynamic effects (average error <5%). Based on two subjects, the statistical models can be used to evaluate local ATAWSS (error <6%) for coronary arteries and for cerebral arteries. An EECP mode planned by the patient-specific treatment strategy can promote an appropriate ATAWSS within a 16 s calculation time. The real-time patient-specific treatment strategy of EECP is expected to improve the long-term outcome for each patient and have potential clinical significance.

Design optimization of the bamboo-inspired foam-filled tube for high-speed train collision energy absorption

This study first developed a novel bamboo-inspired foam-filled tube (BFFT) for potential application in high-speed trains, considering the practical use conditions. The BFFT was initially designed by mimicking the macro and micro characteristics of bamboo culms and understanding their axial crushing mechanical behavior. The key bionic parameters are drawn based on the crashworthiness indices of natural bamboos with various geometric sizes and growth ages. The numerical simulation model of the BFFT under axial impact load was established and verified using simplified super folding element (SSFE) theory and drop-weight experiments. A multi-objective optimization on the BFFT was conducted to find the optimal parameter alternative, integrating experimental design method of the optimal Latin hypercube, the response surface agent model and the non-dominated sorting genetic algorithm (NSGA-II). The crashworthiness performance of the optimized BFFT was compared with the initial design scheme, a conventional circular tube and other existing energy absorbers of rail vehicles. The results indicated that the EA, SEA and IPCF values of the optimized BFFT can be improved by 150.2 %, 63.3 %, and 48.5 %, respectively, when considering the single target requirement. In comparison to the initial design scheme and conventional circular tube, the SEA value of the final optimized BFFT increased by 44.7 % and 53.0 %, respectively. The proposed novel BFFT demonstrated a superior crashworthiness, providing inspiration for enhancing and optimizing passive safety performance of high-speed trains.

Metabolic engineering for optimized CAR-T cell therapy.

The broad effectiveness of T cell-based therapy for treating solid tumour cancers remains limited. This is partly due to the growing appreciation that immune cells must inhabit and traverse a metabolically demanding tumour environment. Accordingly, recent efforts have centred on using genome-editing technologies to augment T cell-mediated cytotoxicity by manipulating specific metabolic genes. However, solid tumours exhibit numerous characteristics restricting immune cell-mediated cytotoxicity, implying a need for metabolic engineering at the pathway level rather than single gene targets. This emerging concept has yet to be put into clinical practice as many questions concerning the complex interplay between metabolic networks and T cell function remain unsolved. This Perspective will highlight key foundational studies that examine the relevant metabolic pathways required for effective T cell cytotoxicity and persistence in the human tumour microenvironment, feasible strategies for metabolic engineering to increase the efficiency of chimeric antigen receptor T cell-based approaches, and the challenges lying ahead for clinical implementation.

Targeting Wnt signaling for improved glioma immunotherapy.

Despite aggressive standard-of-care therapy, including surgery, radiation, and chemotherapy, glioblastoma recurrence is almost inevitable and uniformly lethal. Activation of glioma-intrinsic Wnt/β-catenin signaling is associated with a poor prognosis and the proliferation of glioma stem-like cells, leading to malignant transformation and tumor progression. Impressive results in a subset of cancers have been obtained using immunotherapies including anti-CTLA4, anti-PD-1, and anti-PD-L1 or chimeric antigen receptor (CAR) T cell therapies. However, the heterogeneity of tumors, low mutational burden, single antigen targeting, and associated antigen escape contribute to non-responsiveness and potential tumor recurrence despite these therapeutic efforts. In the current study, we determined the effects of the small molecule, highly specific Wnt/CBP (CREB Binding Protein)/β-catenin antagonist ICG-001, on glioma tumor cells and the tumor microenvironment (TME)-including its effect on immune cell infiltration, blood vessel decompression, and metabolic changes. Using multiple glioma patient-derived xenografts cell lines and murine tumors (GL261, K-Luc), we demonstrated in vitro cytostatic effects and a switch from proliferation to differentiation after treatment with ICG-001. In these glioma cell lines, we further demonstrated that ICG-001 downregulated the CBP/β-catenin target gene Survivin/BIRC5-a hallmark of Wnt/CBP/β-catenin inhibition. We found that in a syngeneic mouse model of glioma (K-luc), ICG-001 treatment enhanced tumor infiltration by CD3+ and CD8+ cells with increased expression of the vascular endothelial marker CD31 (PECAM-1). We also observed differential gene expression and induced immune cell infiltration in tumors pretreated with ICG-001 and then treated with CAR T cells as compared with single treatment groups or when ICG-001 treatment was administered after CAR T cell therapy. We conclude that specific Wnt/CBP/β-catenin antagonism results in pleotropic changes in the glioma TME, including glioma stem cell differentiation, modulation of the stroma, and immune cell activation and recruitment, thereby suggesting a possible role for enhancing immunotherapy in glioma patients.

Multicolor fluorescence microscopy for surgical guidance using a chip-scale imager with a low-NA fiber optic plate and a multi-bandpass interference filter.

In curative-intent cancer surgery, intraoperative fluorescence imaging of both diseased and healthy tissue can help to ensure the successful removal of all gross and microscopic diseases with minimal damage to neighboring critical structures, such as nerves. Current fluorescence-guided surgery (FGS) systems, however, rely on bulky and rigid optics that incur performance-limiting trade-offs between sensitivity and maneuverability. Moreover, many FGS systems are incapable of multiplexed imaging. As a result, clinical FGS is currently limited to millimeter-scale detection of a single fluorescent target. Here, we present a scalable, lens-less fluorescence imaging chip, VISION, capable of sensitive and multiplexed detection within a compact form factor. Central to VISION is a novel optical frontend design combining a low-numerical-aperture fiber optic plate (LNA-FOP) and a multi-bandpass interference filter, which is affixed to a custom CMOS image sensor. The LNA-FOP acts as a planar collimator to improve resolution and compensate for the angle-sensitivity of the interference filter, enabling high-resolution and multiplexed fluorescence imaging without lenses. We show VISION is capable of detecting tumor foci of less than 100 cells at near video framerates and, as proof of principle, can simultaneously visualize both tumors and nerves in ex vivo prostate tissue.

Multitarget Ensemble Docking of Potent Anticancer and Antioxidant Active Compounds from the Acacia auriculiformis and Acacia crassicarpa

Bioactive chemicals derived from Acacia auriculiformis and A. crassicarpa have the potential to be developed as sources of anti-cancer raw materials and antioxidants, given that these plants are fast-growing species with medicinal capability. The in silico method was successful in identifying these bioactive chemicals for the preliminary study. Using an in silico approach, this work aimed to identify the most potent compounds as inhibitors of six cancer and stress oxidative therapy-targeted proteins from these two distinct Acacia species. Seventeen out of the 37 compounds examined exhibited low affinity and satisfied the drug-likeness criterion. Five active chemicals were identified by redocking analysis: auriculoside, 3-(3,4-dihydroxybenzyl)-7-hydroxychroman-4-one, kaempferol 7-O-glucoside, quercetin 7-O-glucoside, and keto-teracacidin. According to simulations of molecular dynamics, molecular motion occurs with a root mean square deviation of less than four and generates at least eleven receptor conformations for 0 to 100 ns. Auriculoside showed the lowest average binding energy against four receptors in colorectal and breast cancer, as determined by ensemble docking, followed by 3-(3,4-dihydroxybenzyl)-7-hydroxychroman-4-one, quercetin 7-O-glucoside, and kaempferol 7-O-glucoside. Auriculoside shown multitarget inhibitory effect against colorectal cancer by inhibiting cyclin dependent kinase-6 and breast cancer by inhibiting epidermal growth factor receptor and mammalian target of rapamycin. Auriculoside has the powerful ability to inhibit glycogen synthase kinase-3 beta, hence regulating oxidative stress. Kaempferol 7-O-glucoside and quercetin 7-O-glucoside also exhibited a possible single protein targeting method against breast cancer. These findings are essential for future research targeted at developing these plants as potent natural therapeutic raw materials and for isolating or synthesizing compounds with anticancer and oxidative stress-regulating antioxidant properties.

Target tracking using video surveillance for enabling machine vision services at the edge of marine transportation systems based on microwave remote sensing

AbstractAutomatic target tracking in emerging remote sensing video-generating tools based on microwave imaging technology and radars has been investigated in this paper. A moving target tracking system is proposed to be low complexity and fast for implementation through edge nodes in a mini-satellite or drone network enabling machine intelligence into large-scale vision systems, in particular, for marine transportation systems. The system uses a group of image processing tools for video pre-processing, and Kalman filtering to do the main task. For testing the system performance, two measures of accuracy and false alarms probability are computed for real vision data. Two types of scenes are analyzed including the scene with single target, and the scene with multiple targets that is more complicated for automatic target detection and tracking systems. The proposed system has achieved a high performance in our tests.

Natural Compound Dioscin Targeting Multiple Cancer Pathways through its High Affinity Binding to B Cell Lymphoma-2.

The study aimed to explore the crucial genes involved in cancer-related biological processes, including EMT, autophagy, apoptosis, anoikis, and metastasis. It also sought to identify common genes among the pathways linked to these biological processes, determine the level of Bcl-2 expression in various types of cancers, and find a potent inhibitor of Bcl-2 among natural compounds. Common genes involved in the pathways related to EMT, autophagy, apoptosis, anoikis, and metastasis were explored, and the level of the most frequently overexpressed gene that was Bcl-2, in various types of cancers was analyzed by gene expression analysis. A set of 102 natural compounds was sorted according to their docking scores using molecular docking and filtering. The top-ranked molecule was chosen for additional molecular dynamics (MD) simulation for 100 ns. Differential gene expression analysis was performed for Dioscin using GEO2R. The study identified four common genes, Bcl-2, Bax, BIRC3, and CHUK, among the pathways linked to EMT, autophagy, apoptosis, anoikis, and metastasis. Bcl-2 was highly overexpressed in many cancers, including Acute Myeloid Leukemia, Diffuse large B cell lymphoma, and Thymoma. The Dioscin structure in the Bcl-2 binding site received the highest docking score and the most relevant interactions. Dioscin's determined binding free energy by MM/GBSA was -52.21 kcal/mol, while the same calculated by MM/PBSA was -9.18 kcal/mol. A p-value of less than 0.05 was used to determine the statistical significance of the analysis performed using GEO2R. It was observed that Dioscin downregulates Bcl-2, BIRC3, and CHUK and upregulates the pro-apoptotic protein Bax. The study concluded that Dioscin has the potential to act as a protein inhibitor, with a noteworthy value of binding free energy and relevant interactions with the Bcl-2 binding site. Dioscin might be a good alternative for targeting multiple cancer pathways through a single target.

Concurrent Learning Approach for Estimation of Pelvic Tilt from Anterior-Posterior Radiograph.

Accurate and reliable estimation of the pelvic tilt is one of the essential pre-planning factors for total hip arthroplasty to prevent common post-operative complications such as implant impingement and dislocation. Inspired by the latest advances in deep learning-based systems, our focus in this paper has been to present an innovative and accurate method for estimating the functional pelvic tilt (PT) from a standing anterior-posterior (AP) radiography image. We introduce an encoder-decoder-style network based on a concurrent learning approach called VGG-UNET (VGG embedded in U-NET), where a deep fully convolutional network known as VGG is embedded at the encoder part of an image segmentation network, i.e., U-NET. In the bottleneck of the VGG-UNET, in addition to the decoder path, we use another path utilizing light-weight convolutional and fully connected layers to combine all extracted feature maps from the final convolution layer of VGG and thus regress PT. In the test phase, we exclude the decoder path and consider only a single target task i.e., PT estimation. The absolute errors obtained using VGG-UNET, VGG, and Mask R-CNN are 3.04 ± 2.49, 3.92 ± 2.92, and 4.97 ± 3.87, respectively. It is observed that the VGG-UNET leads to a more accurate prediction with a lower standard deviation (STD). Our experimental results demonstrate that the proposed multi-task network leads to a significantly improved performance compared to the best-reported results based on cascaded networks.

Sensitivity Enhancement of CO2 Sensors at Room Temperature Based on the CZO Nanorod Architecture.

Cobalt-doped ZnO (CZO) thin films were deposited on glass substrates at room temperature by radio frequency (RF) magnetron sputtering of a single target prepared with ZnO and Co3O4 powders. Changes in the crystallinity, morphology, optical properties, and chemical composition of the CZO thin films were investigated at various sputtering powers of 45, 60, and 75 W. All samples presented a hexagonal wurtzite-type structure with a preferential c-axis at the (002) plane, along with a distinct change in the strain values through X-ray diffraction patterns. Scanning electron and atomic force microscopy revealed uniform and dense deposition of nanorod CZO samples with a high surface roughness (RMS). The Hall mobility and carrier concentration increased with the introduction of Co+ ions into the ZnO matrix, as seen from the Hall effect study. The gradual increase of the power applied on the target source significantly affected the morphology of the CZO thin film, which is reflected in the CO2-sensing performance. The best gas response to CO2 was recorded for CZO-60 W with a response of 1.45 for 500 ppm CO2, and the response/recovery times were 72 and 35 s, respectively. The distinguishing feature of the CZO sensor is its ability to effectively and rapidly detect the CO2 target gas at room temperature (∼27 °C, RT).

Enhancement of the thermoelectric performance of (BiSb)2Te3 films by single target sputtering

In this study, (BiSb)2Te3 thin films were deposited onto glass substrates at a temperature of 300 °C, utilizing radio frequency (RF) sputtering across a range of growth conditions. The primary focus of this investigation was to analyzse the effects of varying RF power, chamber gas pressure, and annealing temperature on the thermoelectric properties of the films, deposited by an exclusively-made single target.Notably, it was observed that increasing the annealing temperature significantly boosted both the deposition rate and grain size. Through carefully optimizsing growth conditions and subsequent annealing procedures, it was discerned that thin films cultivated at higher RF power levels exhibited markedly improved electrical conductivity, attributed to a discernible rise in carrier concentration. Furthermore, films generated under the RF power of 37.5 W showed a noteworthy augmentation in the Seebeck coefficient, recording approximately 147 μV/K. This enhancement in Seebeck coefficient correlated with the attainment of the highest power factor, reaching an impressive 220.57 μW/mK2.

Physically‐Deposited Hole Transporters in Perovskite PV: NiOx Improved with Li/Mg Doping

AbstractNickel oxide (NiOx) has received a lot of attention as an inorganic hole transport material (HTM) in perovskite solar cells (PSCs) during the last decade, owing to its high hole mobility, chemical stability, good optical transparency, and suitable energy levels that align with the valance band of the perovskite absorber methylammonium lead iodide (MAPbI3). This study explores Li and Mg co‐doped NiOx thin films physically‐deposited from developed sputtering targets obtained through cold isostatic pressing and sintering. After sputtering, the structural, elemental, morphological, optical, and electrical properties of the layers are investigated by XRD, XPS, SEM, AFM, UV–vis spectrophotometer, and Hall‐effect; revealing that crystalline, homogeneous, and smooth films are obtained. In particular, improvements in mobility and conductivity values are observed with Li and Mg doping, which contribute to enhanced PSC performance when used as an HTM layer in the glass‐indium tin oxide (ITO)/NiOx‐based HTM/MAPbI3/phenyl butryic acid methyl ester (PCBM)/bathocuproine (BCP)/Ag architecture. The champion solar cell achieves PCE of 15.52%. In addition, the average values of all samples are boosted, JSC (from 13.21 to 15.60 mA cm−2) and FF (from 59.32% to 67.7%), relative to pristine HTM, resulting in a pronounced PCE increment of up to 30% with the HTM film sputtered by a single target of co‐doped material.

Validation of widefield aberrometer for global peripheral aberration scanning

Aberrometers based on Hartmann-Shack wavefront sensing methods have been widely used in the assessment of aberrations in the human eye, a crucial aspect in addressing or adjusting peripheral vision for myopia control, among other applications. Nevertheless, most available aberrometers exhibit limitations such as slow scanning speeds and restricted visual fields when measuring peripheral aberrations. Even the fastest scanning capabilities of commercialized aberrometer are confined to limited visual field and meridians. In this paper, a novel scanning aberrometer for efficient measurement of human eye peripheral aberrations is developed. This instrument allows the measurement of a large visual field angle up to ± 50° and takes all meridian scanning into account, which means it is a widefield aberrometer that can scan the peripheral aberrations globally. Due to the use of the precision motorized rotation stage, both the meridional and visual field angular resolutions of this instrument can be lower to 1°. During the entire measurement process, the subject only needs to focus on a single fixation target. No eye turn or head turn is required. By the instrument installation completed in April 2023, it stands as the only peripheral aberration scanning aberrometer capable of measuring up to a 50° visual field at all meridians using a single fixation target and achieving high angular resolution.

Multitarget scattering imaging based on Nonnegative Matrix Factorization beyond the optical memory effect

Speckle correlation technique is limited by the optical memory effect (OME) range, and aliasing phenomenon occurs in multitarget information beyond the range. Here, we propose a multitarget scattering imaging method based on Nonnegative Matrix Factorization (NMF) beyond the OME, which can separate and interpret the single target information from the aliasing information. Based on the study of the multitarget aliasing speckle autocorrelation model, we apply NMF to unmix the multitarget speckle autocorrelation beyond the OME, and combine with phase retrieval (PR) technology to recover the target. Our approach requires only single-shot speckle information without prior information to realize wide-field multitarget imaging. This work provides potential value for biomedical imaging and astronomical observation, and helps to broaden the application scope of speckle correlation technique.

Multi-target drugs for the treatment of cognitive impairment and fatigue in post-COVID syndrome: focus on Ginkgo biloba and Rhodiola rosea.

Cognitive impairment, depression and (mental) fatigue represent the most frequent neuropsychiatric symptoms of the post-COVID syndrome. Neuroinflammation, oxidative stress and mitochondrial dysfunction have been identified as common pathophysiological mechanisms underlying these symptoms. Attempts to treat post-COVID-associated cognitive impairment and fatigue with different drugs available for other diseases have not yet been successful. One probable explanation could be that these drugs work by one specific mechanism of action only and not in a broad multi-target way. Therefore, they will not address the broad pathophysiological spectrum possibly responsible for cognitive impairment, depression and fatigue in post-COVID syndrome. Notably, nearly all drugs currently under investigation for fatigue in post-COVID syndrome are rather addressing one single target instead of the several pathomechanisms underlying this condition. Contrary to this approach, herbal drugs often consist of many different ingredients with different pharmacological properties and pharmacological targets. Therefore, these drugs might be a promising approach for the treatment of the broad symptomatic presentation and the pathophysiological mechanisms of cognitive impairment and fatigue following a SARS-CoV-2 infection. Of these herbal drugs, extracts of Ginkgo biloba and Rhodiola rosea probably are the best investigated candidates. Their broad pharmacological spectrum in vitro and in vivo includes anti-oxidative, anti-inflammatory, antidepressant as well as properties reducing cognitive impairment and fatigue. In several studies, both drugs showed positive effects on physical and mental fatigue and impaired cognition. Moreover, depressive symptoms were also reduced in some studies. However, even if these results are promising, the data are still preliminary and require additional proof by further studies.

Moving beyond traditional therapies: the role of nanomedicines in lung cancer.

Amidst a global rise in lung cancer occurrences, conventional therapies continue to pose substantial side effects and possess notable toxicities while lacking specificity. Counteracting this, the incorporation of nanomedicines can notably enhance drug delivery at tumor sites, extend a drug's half-life and mitigate inadvertent toxic and adverse impacts on healthy tissues, substantially influencing lung cancer's early detection and targeted therapy. Numerous studies signal that while the nano-characteristics of lung cancer nanomedicines play a pivotal role, further interplay with immune, photothermal, and genetic factors exist. This review posits that the progression towards multimodal combination therapies could potentially establish an efficacious platform for multimodal targeted lung cancer treatments. Current nanomedicines split into active and passive targeting. Active therapies focus on a single target, often with unsatisfactory results. Yet, developing combination systems targeting multiple sites could chart new paths in lung cancer therapy. Conversely, low drug delivery rates limit passive therapies. Utilizing the EPR effect to bind specific ligands on nanoparticles to tumor cell receptors might create a new regime combining active-passive targeting, potentially elevating the nanomedicines' concentration at target sites. This review collates recent advancements through the lens of nanomedicine's attributes for lung cancer therapeutics, the novel carrier classifications, targeted therapeutic modalities and their mechanisms, proposing that the emergence of multi-target nanocomposite therapeutics, combined active-passive targeting therapies and multimodal combined treatments will pioneer novel approaches and tools for future lung cancer clinical therapies.

Abstract IA15: Single cell origins and targeting of genomic instability in breast cancers

Abstract Early whole genome sequencing studies have emphasised the different modes by which breast cancers can evolve. However, bulk NGS tissue analysis obscures mutations that are contemporaneous and/or lead to negative selection, and does not resolve clone specific metrics such as replication rate and fitness. We have developed single cell genome sequencing methods (Laks et al., Cell 2019) to identify large scale copy number-structural (CNA-SV) mutational processes that result in genomic shuffling through the duplication or deletion of chromosomal regions, obscured by bulk tissue analysis. This has revealed the existence and activity of distinct “foreground” mutational processes, i.e. mutational events in single mitoses that are observed directly, before the effects of purifying selection. We discovered that foreground processes are preferentially associated with background patterns of genome instability (Funnell et al., Nature 2022). We also discovered that CNA-SV mutational patterns are associated with relative sensitivity or resistance to platinum, a commonly used DNA targeting agent in TNBC and HGSOC. Our second recent discovery has been the association of CNA-SV mutations with clonal resistance to platinum in TNBC (Salehi et al., Nature 2021). Taken together, we now understand that ongoing CNA-SV mutations contribute to the evolution of fitness landscapes for DNA targeting therapeutics. In parallel work (Xu et al Nat. comms 2017) we have discovered stabilisers of folded DNA guanine stacked bases, G-quadruplexes (G4), to be synthetically lethal in contexts including HR and TMEJ that are underpinned by the single cell processes identified through single genome sequencing. To this end we have recently observed G4-ligand clinical activity in BRCA2 and PALB2 mutated cancers in a phase 1 trial (Hilton et al, Nature communication 2022). Citation Format: Samuel Aparicio. Single cell origins and targeting of genomic instability in breast cancers [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr IA15.