Synthetic viability induces resistance to immune checkpoint inhibitors in cancer cells.

BACKGROUND: Immune checkpoint inhibitors (ICI) have revolutionized the treatment for multiple cancers. However, most of patients encounter resistance. Synthetic viability (SV) between genes could induce resistance. In this study, we established SV signature to predict the efficacy of ICI treatment for melanoma. METHODS: We collected features and predicted SV gene pairs by random forest classifier. This work prioritized SV gene pairs based on CRISPR/Cas9 screens. SV gene pairs signature were constructed to predict the response to ICI for melanoma patients. RESULTS: This study predicted robust SV gene pairs based on 14 features. Filtered by CRISPR/Cas9 screens, we identified 1,861 SV gene pairs, which were also related with prognosis across multiple cancer types. Next, we constructed the six SV pairs signature to predict resistance to ICI for melanoma patients. This study applied the six SV pairs signature to divide melanoma patients into high-risk and low-risk. High-risk melanoma patients were associated with worse response after ICI treatment. Immune landscape analysis revealed that high-risk melanoma patients had lower natural killer cells and CD8+ T cells infiltration. CONCLUSIONS: In summary, the 14 features classifier accurately predicted robust SV gene pairs for cancer. The six SV pairs signature could predict resistance to ICI.

Colorimetric and photothermal dual-mode immunosensor based on Ti3C2Tx/AuNPs nanocomposite with enhanced peroxidase-like activity for ultrasensitive detection of zearalenone in cereals.

A novel peroxidase-like nanozyme has been constructed by decorating two-dimensional Ti3C2Tx nanosheets (Ti3C2Tx NSs) with gold nanoparticles (AuNPs) to develop a colorimetric and photothermal dual-mode immunosensor. The Ti3C2Tx/AuNPs nanocomposite-catalyzed 3,3',5,5'-tetramethylbenzidine (TMB)-H2O2 reaction system produces the one-electron oxidation product of TMB (oxTMB), which exhibits color change and strong near-infrared (NIR) laser-driven photothermal effect at 808 nm laser irradiation. Given these characteristics, the developed immunosensor achieves ultrasensitive dual-mode detection of zearalenone (ZEN) by measuring colorimetric and photothermal signals with a microplate reader and a portable infrared thermometer, respectively. Under optimal working conditions, the limit of detection (LOD) of ZEN is 0.15 pg mL-1 for the colorimetric mode and 0.48 pg mL-1 for the photothermal mode. In the analysis of actual contaminated cereals samples, the test result of this method was consistent with that of UPLC-MS/MS. The proposed colorimetric and photothermal dual-mode immunosensor offers a new strategy for the low-cost detection of hazardous substances. The application of a widely used household infrared thermometer makes the signal readout more convenient, which provides great prospects in food safety and environment inspection applications.

Homogeneous fluorescence immunoassay based on AuNPs (AgNPs) quenching multicolor QDs@hydrogel beads for the simultaneous ultra-sensitive determination of aflatoxin B1 and capsaicinoids in food.

A capsaicinoids (CPCs) broad spectrum monoclonal antibody with same recognition ability to capsaicin (CPC), dihydrocapsaicin (DCPC), nordihydrocapsaicin (NDCPC), and N-vanillylnonanamide (NV) is prepared. Chitosan (CS) hydrogel is used as the carrier of multicolor quantum dots (QDs) to prepare fluorescence hydrogel beads, CPCs and aflatoxin B1 (AFB1) antibody are coupled with fluorescence hydrogel beads to prepare signal probes. Using AuNPs (or AgNPs) as fluorescence quenching agent to prepare quenching probes followed forming a fluorescence quenching test system. Based on optimal group of signal and quenching probes, a novel, simple, convenient, and ultra-sensitive homogeneous fluorescence immunoassay for the simultaneous detection of CPCs and AFB1 is constructed. The limit of detection (LOD) of assay for AFB1 and CPC is 0.00064 µg L-1 and 0.00049 µg L-1, respectively. This method can realize the simultaneous rapid detection of AFB1 and CPCs in food, which provides a new strategy for the identification of kitchen waste oil.

Preparation of a capsaicinoids broad spectrum antibody and its application in non-enzyme immunoassay based on DMSNs@PDA@Pt.

Capsaicinoids (CPCs) is a special ingredient with pungent smell in condiments, which can also be used as an exogenetic marker for kitchen waste oil. Development of immunoassay for CPCs remains a challenging due to relatively difficult preparation of the broad-spectrum antibody (Ab). In this work, a broad-spectrum polyclonal antibody (pAb) which can simultaneously recognize capsaicin (CPC), dihydrocapsaicin (DCPC), nordihydrocapsaicin (NDCPC), and N-vanillylnonanamide (N-V) is produced, and a non-enzyme immunoassay (NISA) based on this Ab, dendritic mesoporous silica nanomaterials (DMSNs), polydopamine (PDA), and high catalytic efficiency of Pt nanoparticles to prepare signal probe (DMSNs@PDA@Pt) is established. Here, the limit of detection (LOD) of NISA for CPC is as low as 0.04 µg L-1. It is worth mentioning that the LOD of the proposed NISA is at least 23 times lower than that of traditional enzyme-linked immunosorbent assay (ELISA) based on horseradish peroxidase (HRP). Moreover, the proposed NISA is applied to detect CPCs in edible oil samples, the result has good consistency with that of ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). The proposed NISA based on DMSN@PDA@Pt and broad-spectrum Ab is an ideal tool for highly effective screening CPCs for kitchen waste oil abuse surveillance.

A fluorescence immunoassay based on GSH destroying MnO2@QDs for the simultaneous ultrasensitive detection of four mycotoxins in cereals.

A novel fluorescence immunoassay based on MnO2 nanoflowers loading multicolor quantum dots and glutathione destroying MnO2 nanoflowers to release quantum dots combined with magnetic separation is developed for rapid, ultra-sensitive, and simultaneous quantitative detection of ochratoxin A, aflatoxin B1, fumonisin B1, and zearalenone in cereal samples. The test linear range of assay is from 0.001 to 200 µg L-1. The limit of detection for ochratoxin A, aflatoxin B1, fumonisin B1, and zearalenone is 0.0001 µg L-1, 0.0001 µg L-1, 0.0003 µg L-1, and 0.0001 µg L-1, respectively. The simultaneous detection of four mycotoxins can be achieve within 30 min. The test results of four mycotoxins in the incurred corn, rice, and oat samples have been confirmed by ultra-performance liquid chromatography tandem mass spectrometry, the differences between results are considered no significantly different (p > 0.05). This multiplexed test scheme has provided a potential analysis strategy for multiple food risk factors.

Fluorescence immunoassay for simultaneous detection typical ß-agonists in animal derived food using blue-green upconversion nanoparticles as labels.

Common typical ß-agonists mainly include ractopamine (RAC), salbutamol (SAL), and clenbuterol (CLB). In view of the harm to human health causes by the ingestion of animal derived food containing ß-agonists, and a series of regulations have been issued to restrict the usage of ß-agonists as growth promoters. In this work, a fluorescence immunoassay is developed for the simultaneous detection of typical ß-agonists based on blue-green upconversion nanoparticles (UCNPs) combine with magnetic separation. Here, blue-green UCNPs act as a signal amplification source, and magnetic polystyrene microspheres (MPMs) act as an ideal separation medium. Based on a competitive form, capture probe competes (RAC-OVA@MPMs and SAL-OVA@MPMs) with targets to bind corresponding signal probe (anti-RAC antibody@NaYF4:Yb, Tm UCNPs and anti-SAL antibody@NaYF4:Yb, Er UCNPs). The fluorescence difference values of the competitive immune-complex obtained via magnetic separation at 483 nm and 550 nm are proportional to concentrations of RAC and SAL, respectively. The immunoassay has the wide detection linear range from 0.001 to 100 µg L-1, and the low limit of detection (LOD) is 5.04 × 10-4 µg L-1 for RAC, 1.97 × 10-4 µg L-1 for SAL, respectively. Meanwhile, use of antibody with same recognition ability for SAL and CLB makes that the fluorescence immunoassay can achieve simultaneous detection of three typical ß-agonists (RAC, SAL, and CLB). This fluorescence immunoassay has good application value and practicability for simultaneous detection of typical ß-agonists in animal derived food.

Mutant RB1 enhances therapeutic efficacy of PARPis in lung adenocarcinoma by triggering the cGAS/STING pathway.

Poly (ADP-ribose) polymerase inhibitors (PARPis) are approved for cancer therapy according to their synthetic lethal interactions, and clinical trials have been applied in non-small cell lung cancer. However, the therapeutic efficacy of PARPis in lung adenocarcinoma (LUAD) is still unknown. We explored the effect of a mutated retinoblastoma gene (RB1) on PARPi sensitivity in LUAD. Bioinformatic screening was performed to identify PARPi-sensitive biomarkers. Here, we showed that viability of LUAD cell lines with mutated RB1 was significantly decreased by PARPis (niraparib, rucaparib, and olaparib). RB1 deficiency induced genomic instability, prompted cytosolic double-stranded DNA (dsDNA) formation, activated the cGAS/STING pathway, and upregulated downstream chemokines CCL5 and CXCL10, triggering immune cell infiltration. Xenograft experiments indicated that PARPi treatment reduced tumorigenesis in RB1-KO mice. Additionally, single-cell RNA sequencing analysis showed that malignant cells with downregulated expression of RB1 had more communications with other cell types, exhibiting activation of specific signaling such as GAS, IFN response, and antigen-presenting and cytokine activities. Our findings suggest that RB1 mutation mediates the sensitivity to PARPis through a synthetic lethal effect by triggering the cGAS/STING pathway and upregulation of immune infiltration in LUAD, which may be a potential therapeutic strategy.

Operational and Financial Impacts of Digital Health Technology: A Study on Canadian Healthcare System during the COVID-19 Pandemic.

During COVID-19, hospital capacity was significantly reduced to limit the spread of the pandemic. The limitations affected the efficiency of service delivery. We examined the effects of pandemic-related challenges on patient experience and hypothesize that digital health implementation increased patient satisfaction. We surveyed nationally aggregated data in hospital occupancy, hospital funding and patient experience, and plotted their correlation. We found digital health to contribute to patient experience and service-delivery effectiveness. We evaluate the benefits of digital health in context of hospital service delivery. Post-COVID-19, we recommend a continued implementation of digital health and offer suggestions to further improve its efficiency and cost-effectiveness.

Freeze-synthesized bio-barcode immunoprobe based multiplex fluorescence immunosensor for simultaneous determination of four nitrofuran metabolites.

Here we have reported a simple and sensitive bio-barcode immunosensor for simultaneous detection of 3-amino-2-oxazolidinone (AOZ), 3-amino-5-morpholinomethyl-2-oxazolidinone (AMOZ), 1-aminohydantoin (AHD), and semicarbazide (SEM) in aquatic products. According to freeze-thaw strategy, four fluorophores (FAM, HEX, ROX, Cy5) labeled single-stranded DNA (ssDNA) were conjugated onto the surface of gold nanoparticles (AuNPs) with corresponding four nitrofuran metabolites monoclonal antibodies (mAbs) for forming four bio-barcode fluorescence immunoprobes. The fluorescence of immunoprobes was quenched by AuNPs. In test progress, the ssDNA with fluorophores were released by adding the dithiothreitol (DTT) and the fluorescence recovered. The immunosensor exhibited sensitive and specific detection of nitrofuran metabolites from 0.05 to 28 µg/L. The limit of detection (LOD) was 0.01, 0.02, 0.02, and 0.05 µg/L for AOZ, AMOZ, AHD, and SEM, respectively. The recoveries of four nitrofuran metabolites in spiked aquatic products have been confirmed by UPLC-MS/MS. The bio-barcode based multiplex immunosensor provides a promising strategy for simultaneous detection of multiple targets.