Sensitivity Enhancement Research Articles

Abstract 691: Preclinical evaluation of valproic acid in combination with radiation in orthotopic models of glioblastoma

Abstract Background: Valproic acid (VPA) is an FDA-approved anti-seizure medication that has been demonstrated to have an anti-tumor and radiosensitization effect on multiple cancer cells including aggressive brain cancer, glioblastoma (GBM). VPA is thought to exert its anti-tumor effects in part through inhibition of histone deacetylases (HDACs), upregulation of apoptosis and autophagy, and disruption of DNA repair mechanisms. Overall survival of patients treated with VPA in combination with TMZ and radiation therapy (RT) was significantly improved compared to historical controls (mOS 29.6 months). Hence, to establish a preclinical benchmark, we investigated the effectiveness of VPA alone and in combination with the radiotherapy in patient-derived xenograft (PDX) models of GBM in vitro and in vivo. Methods: Anti-proliferative effect of VPA in combination with radiation was assessed across multiple GBM cells lines (long-term cultures and PDX lines). Athymic mice were implanted with PDX GBM cells orthotopically and were randomized into four cohorts: vehicle, VPA, IR (6 gy), VPA + IR (6 gy). Animals were treated with 300mg/kg/day of VPA alone or in combination with 6Gy of radiation. Treatments were performed either via intraperitoneal route for 3 consecutive days or via a gastric gavage 5 days on/2 days off for the duration of the study. For pharmacodynamics (PD), animals were sacrificed after 3 days of drug treatment at 2hr, 24hr and 4 days post last dose and processed for immunohistochemical (IHC) analysis for acetylated H3K9/14, KI67, pH2AX, and cleaved caspase 3. Results: VPA treatment demonstrated a dose-dependent decrease in GBM cell viability and enhancement of radiation sensitivity. Pharmacodynamic analysis of tumor-bearing mice demonstrated a significant increase in acetylated H3K9/14 levels upon treatment with combination of VPA and irradiation. Elevation of acetylated H3K9/14 levels was present 2 hours after the administration of the last dose of VPA and it persisted for 4 days. Treatment of mice with irradiation upregulated levels of the apoptosis marker, cleaved caspase 3, which was further enhanced upon VPA and irradiation combination treatment. No reduction in tumor volume or survival benefit was seen in VPA alone or combination cohorts. Conclusion: Consistent with previous reports, treatment of PDX GBM line with VPA reduced cell viability in vitro, increased histone acetylation, and cell death. However, these changes were not sufficient to provide survival benefit in the intracranial model and warrants further investigation into the genetic requirements for radiation sensitization by VPA. Citation Format: Mariya Stavnichuk, Zorana Opachich, Dylan Huttenlocher, James McNamara, Jennifer Molloy, Xu He, Sonam Patel, Nader Sanai, An-Chi Tien, Shwetal Mehta. Preclinical evaluation of valproic acid in combination with radiation in orthotopic models of glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 691.

Near-infrared dual-response fluorescent probe for detection of N2H4 and intracellular viscosity changes in biological samples and various water samples

N2H4 is a common raw material used in the production of pesticides and has good water solubility, so it may contaminate water sources and eventually enter living organisms, causing serious health problems. Viscosity is an important indicator of the cellular microenvironment and an early warning signal for many diseases. The high reactivity of hydrazine depletes glutathione (GSH) in hepatocytes, causing oxidative stress ultimately leading to significant changes in intracellular viscosity and even death. Therefore, it is particularly important to develop an effective method to detect N2H4 and viscosity in environmental and biological systems. On this basis, we developed two fluorescent probes, BDD and BHD, based on xanthene and 2-benzothiazole acetonitrile. The experimental results show that BHD and BDD have good imaging capabilities for N2H4 in cells, zebrafish and Arabidopsis. BHD and BDD also showed sensitive detection and fluorescence enhancement in the near-infrared region when the intracellular viscosity was changed. Notably, the probe BDD has also successfully imaged N2H4 in a variety of real water samples.

Local oscillator port integrated resonator for Rydberg atom-based electric field measurement enhancement

Rydberg atom-based superheterodyne with additional local oscillator (LO) signal is a novel approach to detect electric field with high measured sensitivity. However, the LO signal is often supplied to the atomic vapor cell by free-space illumination, which lacks mobility and integration for practical applications. Here, we present a LO port integrated split-ring resonator for realizing high sensitivity-enhanced electric field measurements. The LO signal is sent directly to the resonator through a parallel-plate waveguide, which is shown to achieve a sensitivity enhancement of 32 dB. The integrated resonator has an electrical size of 0.088λ and the feed port S11 reaches −38.2 dB.

An In Vitro Examination of Whether Kratom Extracts Enhance the Cytotoxicity of Low-Dose Doxorubicin against A549 Human Lung Cancer Cells.

Doxorubicin is an effective chemotherapeutic agent in the treatment of solid hematological and non-hematological carcinoma. However, its long-term usage could result in side effects, such as cardiomyopathy, chronic heart failure, neurotoxicity and cancer cell resistance. In this study, we reported the sensitivity enhancement of A549 human lung cancer cells on doxorubicin at a low dose (0.1 ppm) in combination with 10-60 ppm of crude and alkaloid extracts derived from the leaves of Kratom (Mitragyna speciosa (Korth.) Havil. Rubiaceae). A549 cancer cell lines were insensitive to the crude extract containing low mitragynine (MG) (4-5%), while these cells were moderately inhibited by the alkaloid extract containing 40-45% MG (IC50 of 48-55 ppm). The alkaloid extract was found to inhibit A549 cancer cells via apoptosis as suggested by the higher relative fluorescence intensity with Annexin compared to that in propidium iodide (PI), i.e., a positive Annexin and a negative PI. The combination of crude extract and doxorubicin sensitized A549 cancer cells to doxorubicin by 1.3 to 2.4 times, while the combination with the alkaloid induced a 2.6- to 3.4-fold increase in sensitivity. The calculated combination index (CI) for doxorubicin with the crude and alkaloid extracts was 0.6 and 0.3, respectively, showing potential synergistic combinations to reduce the level of dosage of doxorubicin used in chemotherapy. In addition, the synergistic enhancement effect of crude extract on the cytotoxic activity of doxorubicin provides insights into the plausibility of non-alkaloids to influence the biological activities of Kratom.

Screening and diagnosis of respiratory diseases using metamaterial based sensitive terahertz impedance spectroscopy

Utilizing LC resonant metamaterials (MM) for terahertz (THz) impedance spectroscopy has opened new avenues for detection of biomolecules and nanoparticles. A recent revelation highlights the pivotal role of coupling between MM resonance and Fabry-Pérot (FP) oscillations of the substrate. This interaction significantly influences the observed spectral shift (ΔF), thereby enhancing the overall sensitivity. In this work, we utilize the FP-MM optical decoupling physics for sensitivity enhancement to detect bio-particles at extremely low concentrations, thereby overcoming the particle detection limit. After implementing these innovations, we discovered that this technology can be leveraged to detect and screen patients infected with the omicron variant of SARS-CoV-2 and other lung related diseases using exhaled breath from patients. Upon achieving excellent agreement between simulations and experimental spectroscopic data, we have successfully detected and screened multiple respiratory-related diseases from the exhaled breath collected on the metasurface in a breathalyzer configuration. We obtained significant ΔF even with ultra-low concentrations of bio-particles and demarcated the ranges of ΔF for different lung diseases that do no overlap and are not constrained by any limit of detection. This work reveals new prospects for diagnosis and screening of multiple respiratory-related diseases with a single and prompt breath test.

Long-term stable pH sensor array with synergistic bilayer structure for 2D real-time mapping in cell culture monitoring

Pursuing accurate, swift, and durable pH sensors is important across numerous fields, encompassing healthcare, environmental surveillance, and agriculture. In particular, the emphasis on real-time pH monitoring during cell cultivation has become increasingly pronounced in the current scientific environment—a crucial element being diligently researched to ensure optimal cell production. Both polyaniline (PANi) and iridium oxide (IrOx) show their worth in pH sensing, yet they come with challenges. Single-PANi-layered pH sensors often grapple with diminished sensitivity and lagging responses, while electrodeposited IrOx structures exhibit poor adhesion, leading to their separation from metallic substrates—a trait undesirable for a consistently stable, long-term pH sensor. This paper introduces a bi-layered PANi-IrOx pH sensor, strategically leveraging the advantages of both materials. The results presented here underscore the sensitivity enhancement of binary-phased framework, faster response time, and more robust structure than prior work. Through this synergistic strategy, we demonstrate the potential of integrating different phases to overcome the inherent constraints of individual materials, setting the stage for advanced pH-sensing solutions.

Opening windows with isospin-violating dark matter

We consider the effect of isospin-violating dark matter-nucleon interactions on direct detection constraints in the regime of small dark matter mass and large scattering cross section. Isospin-violation can lead to both reductions in sensitivity (due to a reduced cross section for scattering with nuclei in the detector) and enhancements in sensitivity (due to a reduced cross section for scattering in the overburden). Isospin-violating effects can thus open up some closed regions of parameter space, while closing off other regions.

Refueling convenience and range satisfaction in electric mobility: Investigating consumer willingness to use battery swap services for electric vehicles

Battery swap service (BSS) is a game-changing innovation for achieving electric vehicle (EV) refueling, driving range satisfaction, and convenience. BSS is an avenue for swapping a worn-out EV battery for a pre-charged one, eliminating the long charging times of batteries. However, consumer adoption of BSS is overlooked, lacking empirical support. BSS is encouraged as it makes clean ‘fuel’ readily available for EV use. Consumer willingness to patronize BSS is pivotal to EV usage, sustainable transport, and pollution mitigation. Consequently, the innovation diffusion theory is extended with attitude, perceived risk, green self-identity, and task-technology fit to investigate consumer willingness to use BSS. Utilizing a partial least squares-structural equation model (PLS-SEM), 618 responses were analyzed. The outcome revealed that relative advantage, compatibility, attitude, green self-identity, and task-technology fit positively impacted willingness to use BSS. Perceived risk had a significant adverse effect on willingness to use BSS. Attitude mediated the impact of relative advantage and task-technology fit. Also, perceived risk negatively affected attitude. Further, ANOVA analysis confirmed the impact of consumer demography on the willingness to use BSS. Policies involving swapping standardization and synchronization, public sensitization, monetary incentives, and battery performance enhancement are recommended for enhancing BSS acceptance, usage, and proliferation.

ClonoScreen3D – A Novel 3-Dimensional Clonogenic Screening Platform for Identification of Radiosensitizers for Glioblastoma

PurposeGlioblastoma (GBM) is a lethal brain tumor. Standard of care treatment comprising surgery, radiation and chemotherapy results in median survival rates of 12-15 months. Molecular targeted agents identified using conventional two-dimensional (2D) in vitro models of GBM have failed to improve outcome in patients, rendering such models inadequate for therapeutic target identification. A previously developed 3D GBM in vitro model that recapitulates key GBM clinical features and responses to molecular therapies was investigated for utility for screening novel radiation-drug combinations using gold-standard clonogenic survival as readout. ResultsPatient-derived GBM cell lines were optimized for inclusion in a 96-well plate 3D clonogenic screening platform, ClonoScreen3D. Radiation responses of GBM cells in this system were highly reproducible and comparable to those observed in low-throughout 3D assays. The screen methodology provided quantification of candidate drug single agent activity (EC50) and the interaction between drug and radiation (radiation interaction ratio, RIR). The PARP inhibitors talazoparib, rucaparib and olaparib, each showed a significant interaction with radiation by ClonoScreen3D and were subsequently confirmed as true radiosensitizers by full clonogenic assay. Screening a panel of DNA damage response inhibitors revealed the expected propensity of these compounds to interact significantly with radiation (13/15 compounds). A second screen assessed a panel of compounds targeting pathways identified by transcriptomic analysis and demonstrated single agent activity and a previously unreported interaction with radiation of dinaciclib and cytarabine (RIR 1.28 and 1.90, respectively). These compounds were validated as radiosensitizers in full clonogenic assays (sensitizer enhancement ratio 1.47 and 1.35, respectively). ConclusionsThe ClonoScreen3D platform was demonstrated to be a robust method to screen for single agent and radiation-drug combination activity. Using gold-standard clonogenicity, this assay is a tool for identification of radiosensitizers. We anticipate this technology will accelerate identification of novel radiation-drug combinations with genuine translational value.

A toroidal SAW gyroscope with focused IDTs for sensitivity enhancement

A surface acoustic wave (SAW) gyroscope measures the rate of rotational angular velocity by exploiting a phenomenon known as the SAW gyroscope effect. Such a gyroscope is a great candidate for application in harsh environments because of the simplification of the suspension vibration mechanism necessary for traditional microelectromechanical system (MEMS) gyroscopes. Here, for the first time, we propose a novel toroidal standing-wave-mode SAW gyroscope using focused interdigitated transducers (FIDTs). Unlike traditional SAW gyroscopes that use linear IDTs to generate surface acoustic waves, which cause beam deflection and result in energy dissipation, this study uses FIDTs to concentrate the SAW energy based on structural features, resulting in better focusing performance and increased SAW amplitude. The experimental results reveal that the sensitivity of the structure is 1.51 µV/(°/s), and the bias instability is 0.77°/s, which are improved by an order of magnitude compared to those of a traditional SAW gyroscope. Thus, the FIDT component can enhance the performance of the SAW gyroscope, demonstrating its superiority for angular velocity measurements. This work provides new insights into improving the sensitivity and performance of SAW gyroscopes.

Exceptional Lithography Sensitivity Boosted by Hexafluoroisopropanols in Photoresists.

Advanced lithography requires highly sensitive photoresists to improve the lithographic efficiency, and it is critical, yet challenging, to develop high-sensitivity photoresists and imaging strategies. Here, we report a novel strategy for ultra-high sensitivity using hexafluoroisopropanol (HFIP)-containing fluoropolymer photoresists. The incorporation of HFIP, with its strong electrophilic property and the electron-withdrawing effect of the fluorine atoms, significantly increases the acidity of the photoresist after exposure, enabling imaging without conventional photoacid generators (PAGs). The HFIP-containing photoresist has been evaluated by electron beam lithography to achieve a trench of ~40 nm at an extremely low dose of 3 μC/cm2, which shows a sensitivity enhancement of ~10 times compared to the commercial system involving PAGs, revealing its high sensitivity and high-resolution features. Our results demonstrate a new type of PAGs and a novel approach to higher-performance imaging beyond conventional photoresist performance tuning.

Design and Simulation of SPR Sensors by Employing Silicon and Silicon-Nitride With Mono and Bimetal Layers for Sensitivity Enhancement

Design and Simulation of SPR Sensors by Employing Silicon and Silicon-Nitride With Mono and Bimetal Layers for Sensitivity Enhancement

One-step online analysis of antibiotics in highly saline seawater by nano-based slug-flow microextraction

The transition to mass spectrometry (MS) in the analysis of antibiotics in the marine environment is highly desirable, particularly in the enhancement of sensitivity for high-salinity (3.5 wt%) seawater samples. However, the persistence of complex operational procedures poses substantial challenges to this transition. In this study, a rapid method for the online analysis of antibiotics in seawater samples via nano-electrospray ionization (nESI) MS based on slug-flow microextraction (SFME) has been proposed. Comparisons with other methods, complex laboratory setups for sample processing are now seamlessly integrated into a single online step, completing the entire process, including desalination and detection, SFME–nESI–MS provides faster results in less than 2 min while maintaining sensitivity comparable to that of other detection methods. Using SFME–nESI, six antibiotics in high-salinity (3.5 wt%) seawater samples have been determined in both positive and negative ion modes. The proposed method successfully detected clarithromycin, ofloxacin, and sulfadimidine in seawater within a linear range of 1–1000 ng mL−1 and limit of detection (LOD) of 0.23, 0.06, and 0.28 ng mL−1, respectively. The method recovery was from 92.8% to 107.3%, and the relative standard deviation was less than 7.5%. In addition, the response intensity of SFME–nESI-treated high-salinity (3.5 wt%) samples surpassed that of untreated medium-salinity (0.35 wt%) samples by two to five orders of magnitude. This advancement provides an exceptionally simplified protocol for the online rapid, highly sensitive, and quantitative determination of antibiotics in high-salinity (3.5 wt%) seawater.

Dosimetric properties of Cr–La, Cr–Cu, and Cu–La ions codoped Ca9 Al (PO4)7 nanostructure

In the present work, Cr–La, Cr–Cu, and Cu–La ions codoped Ca9Al (PO4)7 nanostructures (symbolized as Cr–La, Cr–Cu, and Cu–La) were prepared using the sol-gel method for their dosimetric properties. X-ray diffraction (XRD) and transmission electron microscopy (TEM) results reflected the existence of the nanoparticle structure. This confirmed the successful sol-gel preparation method used. The surface morphological properties of the prepared samples were scrutinized by scanning electron microscopy (SEM). The presence and distribution of the constituent elements of the samples were determined using energy-dispersive X-ray (EDX) spectroscopy. The thermoluminescence (TL) sensitivity enhancement and homogenous properties of the prepared samples were assessed using a γ-radiation dose of 5 Gy. TL sensitivity of the Cr–Cu sample was found to be optimum. The relative standard deviations (RSD) of the homogenous study were found to be 6.5, 5.7, and 3.9% for Cr–La, Cr–Cu, and Cu–La, respectively, which were acceptable according to the ISO requirements (<10%). The dose-linearity response was investigated in 0.5 up to 20 Gy γ-dose ranges. The sample Cr–Cu had a good dose-linearity of up to 20 Gy while the others (Cr–La and Cu–La samples) had a dose-linearity of up to 13 Gy. The threshold doses (MDD) of the Cr–La, Cr–Cu, and Cu–La samples were computed and found to be approximately 110, 32, and 134 μGy, respectively. The photon attenuation parameters of the prepared samples were computed using the Phy-X PSD program, and the acquired data showed that the Ca9Al (PO4)7 composition had bone-equivalent material characteristics. Results of the dosimetric properties of Cr–La, Cr–Cu, and Cu–La co-doped Ca9Al (PO4)7 samples suggested that these compositions had potentially excellent TL characteristics to be used in various dosimetric applications across a broad range of gamma doses.

Covalently construction of C-GSH-AuNCs@UiO-66-NH2 composites as an efficient turn-on fluorescence sensor for UO22+

Due to the continuous expansion of the nuclear power industry, the exploitation of uranium resources has led to the discharge of large quantities of uranium-rich wastewater into the environment, which poses a major threat to the environment and human health. Rapid detection of uranium in water bodies is of great significance for early warning of uranium contamination in the environment, safe discharge and real-time regulation of nuclear waste, and sustainable development of energy and ecological environment. Herein, we report a new “turn-on” fluorescent sensor for the detection of UO22+ in aqueous solutions. The fluorescent sensor was obtained by covalently bonding UiO-66-NH2 with gold nanoclusters GSH-AuNCs and showed a sensitive fluorescence enhancement response to UO22+ at low solid-liquid ratio, with a detection limit of 15.3 nmol L−1. With the advantages of intuitive visual detection, reusability and easy separation, the sensitive fluorescence sensor has great potential for the detection of UO22+ in aqueous solutions.

Click Reaction-Mediated Fluorescent Immunosensor Based on Cu-MOF Nanoparticles for Ultrasensitive and High-Throughput Detection of Aflatoxin B1 in Food Samples.

Due to the high toxicity of aflatoxin B1 and its risks to human health, we developed a click reaction-mediated automated fluorescent immunosensor (CAFI) for sensitive detection of aflatoxin B1 based on the Cu(I)-catalyzed click reaction. With its large specific surface area, a copper-based metal-organic framework (Cu-MOF) was synthesized to adsorb and enrich the copper ion (Cu(II)) and then load the complete antigen (BSA-AFB1). After the immunoreaction, Cu(II) inside the Cu-MOF-Antigen conjugate would be reduced to Cu(I) in the presence of sodium ascorbate, which triggered the click reaction between the fluorescent donor-modified DNA and the receptor-modified complementary DNA to lead to a fluorescence signal readout. The whole reaction steps were finished by the self-developed automated immunoreaction device. This CAFI method showed a limit of detection (LOD) of 0.48 pg/mL as well as a 670-fold enhancement in sensitivity compared to conventional ELISA, revealing its great potential in practical applications and automated detection.

Improving the Performance of Selective Solid-State Nanopore Sensing Using a Polyhistidine-Tagged Monovalent Streptavidin.

Solid-state (SS-) nanopore sensing has gained tremendous attention in recent years, but it has been constrained by its intrinsic lack of selectivity. To address this, we previously established a novel SS-nanopore assay that produces translocation signals only when a target biotinylated nucleic acid fragment binds to monovalent streptavidin (MS), a protein variant with a single high-affinity biotin-binding domain. While this approach has enabled selective quantification of diverse nucleic acid biomarkers, sensitivity enhancements are needed to improve the detection of low-abundance translational targets. Because the translocation dynamics that determine assay efficacy are largely governed by constituent charge characteristics, we here incorporate a polyhistidine-tagged MS (hMS) to alter the component detectability. We investigate the effects of buffer pH, salt concentration, and SS-nanopore diameter on the performance with the alternate reagent, achieve significant improvements in measurement sensitivity and selectivity, and expand the range of device dimensions viable for the assay. We used this improvement to detect as little as 1 nM miRNA spiked into human plasma. Overall, our findings improve the potential for broader applications of SS-nanopores in the quantitative analyses of molecular biomarkers.

Sensitivity Enhancement in Photoconductive Light Field Sampling

AbstractThe emerging field of lightwave electronics is driving optoelectronic information processing beyond current classical limitations and has the potential to eventually reach petahertz frequencies. One of the major obstacles in reaching not only higher switching frequencies but also higher repetition rates with low‐power light sources is the efficiency of related devices. A device is presented based on a multilayered material that shows a 13‐fold enhancement in terms of converting light to electric current compared to bulk solids. Furthermore, the device exhibits an almost flat intensity response within its working range. The outstanding properties of engineered multilayered devices promise to push technology for lightwave electronics applications.

Sensitivity enhancement of bimodal waveguide interferometric sensor based on regional mode engineering.

In this paper, we propose a novel bimodal waveguide based on regional mode engineering (BiMW-RME). Leveraging the orthogonality of the guided modes, the form of patterned SiO2 cladding on the bimodal waveguide can reduce the interaction between the reference mode and the analyte, thereby significantly improving sensitivity. The proposed BiMW-RME sensor experimentally demonstrates a phase sensitivity of 2766 π rad/RIU/cm and a detection limit of 2.44×1-5 RIU. The sensitivity is 2.7 times higher than that of the conventional BiMW sensor on the same SOI platform. The proposed design strategy demonstrates a significant improvement in the sensor's sensitivity, presenting a novel approach to enhancing common-path interferometric sensor performance.

Revisiting the Effect of Leptin on Alzheimer Disease and Parkinson Disease: The Role of Insulin Sensitivity.

Studies have indicated a link between leptin, Alzheimer disease (AD), and Parkinson disease (PD). However, the causal relationship among them remains not well established due to confounders and reverse causation. This Mendelian randomization (MR) study was performed to evaluate the impact and potential mechanism of leptin and its soluble receptor on AD and PD. Utilizing genome-wide association studies summary-level data, a comprehensive MR was conducted to assess the causal effect of leptin and soluble leptin receptor (sLEPR) on AD and PD. Additionally, we also explored the role of body mass index (BMI) and insulin sensitivity index (ISI) in using the multivariable MR. The primary analysis was performed using the inverse variance-weighted method. Pooled estimates showed that genetically proxied higher leptin levels was significantly associated with a decreased risk of AD (OR 0.838, 95% CI 0.741-0.948, P = .005), but not PD. In contrast, no significant associations were observed between sLEPR levels, AD, and PD. Moreover, the effect of leptin on AD was attenuated to null after adjustment of ISI (OR 0.879, 95% CI 0.758-1.018, P = .086), but not BMI. There was no causal impact of AD and PD on circulating levels of leptin and sLEPR, indicating the absence of reverse causation. Sensitivity analyses confirmed the robustness of these associations, with no obvious pleiotropy and heterogeneity. The study offers evidence supporting a potential protective effect of leptin in AD, but not PD, via the enhancement of insulin sensitivity. Our findings underscore the distinct roles of leptin in AD and PD.