Bacteria‐mediated tumor therapy (BMTT) has been known for decades; however, its clinical use is inhibited by its association with infections. To address this issue, a spiky, bacterium‐like ...metal–organic framework (MOF), which can replicate the functional responses of BMTT without its adverse side‐effects, is proposed. MOFs are synthesized in a solvothermal reaction of aluminum sulfate, ruthenium chloride hydrate, and 2‐aminoterephthalic acid; they have a spherical morphology or many nanospikes on their surfaces, depending on the reaction temperature. Both spherical and spiky MOFs can function as photothermal agents, converting absorbed optical energy into local heat. Owing to their higher surface area of interaction, spiky MOFs are more easily phagocytosed by macrophages than are spherical MOFs, strengthening their immune responses. Moreover, when injected intratumorally, spiky MOFs reside significantly longer than spherical ones, enabling their use in repeated photothermal treatments. The combination of in situ vaccination with intratumorally injected bacterium‐like MOFs under exposure to an near‐infrared laser and the immune checkpoint blockade of systemically administered αPD‐1 is evaluated in tumor‐bearing mice. The results indicate that the checkpoint blockade acts synergistically with in situ vaccination to provide diverse antitumor functions of BMTT, destroying a primary tumor and suppressing tumor recurrence and metastasis.
The combination of in situ vaccination by intratumorally injected bacterium‐like MOFs under NIR exposure and the checkpoint blockade of systemically administered αPD‐1 is used to enable the diverse antitumor functions of bacteria‐mediated tumor therapy. The results indicate that the checkpoint blockade acts synergistically with in situ vaccination to strengthen immune memory responses, yielding remarkable antitumor efficacy.
The ongoing COVID-19 pandemic has caused more than 193,825 deaths during the past few months. A quick-to-be-identified cure for the disease will be a therapeutic medicine that has prior use ...experiences in patients in order to resolve the current pandemic situation before it could become worsening. Artificial intelligence (AI) technology is hereby applied to identify the marketed drugs with potential for treating COVID-19.
An AI platform was established to identify potential old drugs with anti-coronavirus activities by using two different learning databases; one consisted of the compounds reported or proven active against SARS-CoV, SARS-CoV-2, human immunodeficiency virus, influenza virus, and the other one containing the known 3C-like protease inhibitors. All AI predicted drugs were then tested for activities against a feline coronavirus in in vitro cell-based assay. These assay results were feedbacks to the AI system for relearning and thus to generate a modified AI model to search for old drugs again.
After a few runs of AI learning and prediction processes, the AI system identified 80 marketed drugs with potential. Among them, 8 drugs (bedaquiline, brequinar, celecoxib, clofazimine, conivaptan, gemcitabine, tolcapone, and vismodegib) showed in vitro activities against the proliferation of a feline infectious peritonitis (FIP) virus in Fcwf-4 cells. In addition, 5 other drugs (boceprevir, chloroquine, homoharringtonine, tilorone, and salinomycin) were also found active during the exercises of AI approaches.
Having taken advantages of AI, we identified old drugs with activities against FIP coronavirus. Further studies are underway to demonstrate their activities against SARS-CoV-2 in vitro and in vivo at clinically achievable concentrations and doses. With prior use experiences in patients, these old drugs if proven active against SARS-CoV-2 can readily be applied for fighting COVID-19 pandemic.
Most cancer vaccines under development are associated with defined tumor antigens rather than with all antigens of whole tumor cells, limiting the anti-tumor immune responses that they elicit. This ...work proposes an immunomodulator (R848)-loaded nanoparticle system (R848@NPs) that can absorb near-infrared light (+NIR) to cause low-temperature hyperthermia that interacts synergistically with its loaded R848 to relieve the tumor-mediated immunosuppressive microenvironment, generating robust anti-tumor memory immunity. In vitro results reveal that the R848@NPs could be effectively internalized by dendritic cells, causing their maturation and the subsequent regulation of their anti-tumor immune responses. Post-treatment observations in mice in which tumors were heat-treated at high temperatures reveal that tumor growth was significantly inhibited initially but not in the longer term, while low-temperature hyperthermia or immunotherapy alone simply delayed tumor growth. In contrast, a combined therapy that involved low-temperature hyperthermia and immunotherapy using R848@NPs/+NIR induced a long-lasting immunologic memory and consequently inhibited tumor growth and prevented cancer recurrence and metastasis. These results suggest that the method that is proposed herein is promising for generating cancer vaccines in situ, by using the tumor itself as the antigen source and the introduced R848@NPs/+NIR to generate a long-term anti-tumor immunity, for personalized immunotherapy.
There are racial/ethnic disparities in breast cancer mortality may be attributed to differences in receipt of adjuvant cancer treatment. Our purpose was to determine whether the mortality disparities ...could be explained by racial/ethnic differences in long-term adherence to adjuvant endocrine therapy (AET).
We conducted a retrospective cohort study with the Texas Cancer Registry and Medicaid claims-linked dataset of women (20-64 years) diagnosed with local and regional breast cancer who filled a prescription for AET from 2000-2008. Adherence to AET was measured at three time points (1-, 3-, and 5-year adherence) using a value for the percentage of medication filled for each period divided by the total number of possible prescriptions prescribed (Medication Possession Ratio, MPR). We created a binary variable of adherence (MPR≥80%). We performed multivariable logistic regressions to assess racial differences for the odds of AET adherence and Cox proportional hazard models to determine the risk of mortality adjusting for potential confounding variables of SES, comorbidities, tumor prognostic factors, and other cancer treatment.
Of the 1,497 women with breast cancer who initiated AET, 56.9%, 42.3%, and 33.3% were adherent for 1, 3, and 5-years, respectively. Hispanics compared to non-Hispanic whites did differ in the proportion that were adherent to 5-years of AET. In the adjusted analysis for long-term adherence to AET, Hispanics did not have a significantly increased risk of death compared to non-Hispanic white patients (HR: 1.13, 95% CI: 0.58-2.21). However, black compared to non-Hispanic white patients had significantly lower odds of three-year adherence (OR: 0.45, 95% CI: 0.28-0.73). After controlling for 5-year adherence to AET, the risk of death for black compared to non-Hispanic white patients was 12% lower (HR: 1.90; 95% CI: 1.03-3.51) and in the fully adjusted model, the disparity was reduced and no longer significant (OR: 1.86, 95% CI: 0.94-3.66).
Long-term adherence in the Medicaid population is suboptimal and racial/ethnic differences in AET adherence may partially explain disparities in mortality. This study underscores the critical need to ensure long-term adherence to AET for all racial/ethnic groups to decrease disparities in mortality.
Efficient cardiac function requires synchronous ventricular contraction. After myocardial infarction, the nonconductive nature of scar tissue contributes to ventricular dysfunction by electrically ...uncoupling viable cardiomyocytes in the infarct region. Injection of a conductive biomaterial polymer that restores impulse propagation could synchronize contraction and restore ventricular function by electrically connecting isolated cardiomyocytes to intact tissue, allowing them to contribute to global heart function.
We created a conductive polymer by grafting pyrrole to the clinically tested biomaterial chitosan to create a polypyrrole (PPy)-chitosan hydrogel. Cyclic voltammetry showed that PPy-chitosan had semiconductive properties lacking in chitosan alone. PPy-chitosan did not reduce cell attachment, metabolism, or proliferation in vitro. Neonatal rat cardiomyocytes plated on PPy-chitosan showed enhanced Ca(2+) signal conduction in comparison with chitosan alone. PPy-chitosan plating also improved electric coupling between skeletal muscles placed 25 mm apart in comparison with chitosan alone, demonstrating that PPy-chitosan can electrically connect contracting cells at a distance. In rats, injection of PPy-chitosan 1 week after myocardial infarction decreased the QRS interval and increased the transverse activation velocity in comparison with saline or chitosan, suggesting improved electric conduction. Optical mapping showed increased activation in the border zone of PPy-chitosan-treated rats. Echocardiography and pressure-volume analysis showed improvement in load-dependent (ejection fraction, fractional shortening) and load-independent (preload recruitable stroke work) indices of heart function 8 weeks after injection.
We synthesized a biocompatible conductive biomaterial (PPy-chitosan) that enhances biological conduction in vitro and in vivo. Injection of PPy-chitosan better maintained heart function after myocardial infarction than a nonconductive polymer.
Following myocardial infarction (MI), necrotic cardiomyocytes (CMs) are replaced by fibroblasts and collagen tissue, causing abnormal electrical signal propagation, desynchronizing cardiac ...contraction, resulting in cardiac arrhythmia. In this work, a conductive polymer, poly-3-amino-4-methoxybenzoic acid (PAMB), is synthesized and grafted onto non-conductive gelatin. The as-synthesized PAMB-G copolymer is self-doped in physiological pH environments, making it an electrically active material in biological tissues. This copolymer is cross-linked by carbodiimide to form an injectable conductive hydrogel (PAMB-G hydrogel). The un-grafted gelatin hydrogel is prepared in a similar manner as a control. Both test hydrogels not only provide an optimal matrix for CM adhesion and growth but also maintain CM morphology and functional proteins. The conductivity of PAMB-G hydrogel is ca. 12 times higher than that of gelatin hydrogel. Microelectrode array analyses reveal that a heart placed on the PAMB-G hydrogel has a higher field potential amplitude than that placed on the gelatin hydrogel and can pass current from one heart to excite another heart at a distance. The injection of PAMB-G hydrogel into the scar zone following an MI in a rat heart improves electrical impulse propagation over that in a heart that has been treated with gelatin hydrogel, and synchronizes heart contraction, leading to preservation of the ventricular function and reduction of cardiac arrhythmia, demonstrating its potential for use in treating MI.
Although dietary selenium (Se) deficiency or excess induces type 2 diabetes–like symptoms in mice, suboptimal body Se status usually causes no symptoms but may promote age-related decline in overall ...health.
We sought to determine the dietary Se requirement for protection against type 2 diabetes–like symptoms in mice.
Thirty mature (aged 4 mo) male C57BL/6J mice were fed a Se-deficient torula yeast AIN-93M diet supplemented with Na2SeO4 in graded concentrations totaling 0.01 (basal), 0.04, 0.07, 0.10, and 0.13 (control) mg Se/kg for 4 mo (n = 6) until they were middle-aged (8 mo). Droplets of whole blood were used to determine glucose tolerance and insulin sensitivity in the mice from ages 5 to 8 mo. Postmortem serum, liver, and skeletal muscle were collected to assay for selenoprotein expression and markers of glucose metabolism. Data were analyzed by 1-way ANCOVA with or without random effects for time-repeated measurements using live mice or postmortem samples, respectively.
Compared with control, the consumption of basal diet increased (P < 0.05) fasting serum insulin (95% CI: 52%, 182%) and leptin (95% CI: 103%, 118%) concentrations in middle-aged mice. Dietary Se insufficiency decreased (P < 0.05) 1) glucose tolerance (13–79%) and insulin sensitivity (15–65%) at ≤0.10 mg Se/kg; 2) baseline thymoma viral proto-oncogene phosphorylation on S473 (27–54%) and T308 (22–46%) at ≤0.10 and ≤0.07 mg Se/kg, respectively, in the muscle but not the liver; and 3) serum glutathione peroxidase 3 (51–83%), liver and muscle glutathione peroxidase 1 (32–84%), serum and liver selenoprotein P (28–42%), and liver and muscle selenoprotein H (39–48%) and selenoprotein W (16–73%) protein concentrations at ≤0.04, ≤0.10, ≤0.07, and ≤0.10 mg Se/kg, respectively.
Mice fed diets containing ≤0.10 mg Se/kg display impaired glucose tolerance and insulin sensitivity, suggesting increased susceptibility to type 2 diabetes by suboptimal Se status at levels ≤23% of nutritional needs.
The inhibition of FMS-like tyrosine kinase 3 (FLT3) activity using small-molecule inhibitors has emerged as a target-based alternative to traditional chemotherapy for the treatment of acute myeloid ...leukemia (AML). In this study, we report the use of structure-based virtual screening (SBVS), a computer-aided drug design technique for the identification of new chemotypes for FLT3 inhibition. For this purpose, homology modeling (HM) of the DFG-in FLT3 structure was carried using two template structures, including PDB ID: 1RJB (DFG-out FLT3 kinase domain) and PDB ID: 3LCD (DFG-in CSF-1 kinase domain). The modeled structure was able to correctly identify known DFG-in (SU11248, CEP-701, and PKC-412) and DFG-out (sorafenib, ABT-869 and AC220) FLT3 inhibitors, in docking studies. The modeled structure was then used to carry out SBVS of an HTS library of 125,000 compounds. The top scoring 97 compounds were tested for FLT3 kinase inhibition, and two hits (BPR056, IC50 = 2.3 and BPR080, IC50 = 10.7 μM) were identified. Molecular dynamics simulation and density functional theory calculation suggest that BPR056 (MW: 325.32; cLogP: 2.48) interacted with FLT3 in a stable manner and could be chemically optimized to realize a drug-like lead in the future.
Abstract Myocardial infarction is often associated with abnormalities in electrical function due to a massive loss of functioning cardiomyocytes. This work develops a mesh, consisting of aligned ...composite nanofibers of polyaniline (PANI) and poly(lactic-co-glycolic acid) (PLGA), as an electrically active scaffold for coordinating the beatings of the cultured cardiomyocytes synchronously. Following doping by HCl, the electrospun fibers could be transformed into a conductive form carrying positive charges, which could then attract negatively charged adhesive proteins (i.e. fibronectin and laminin) and enhance cell adhesion. During incubation, the adhered cardiomyocytes became associated with each other and formed isolated cell clusters; the cells within each cluster elongated and aligned their morphology along the major axis of the fibrous mesh. After culture, expression of the gap-junction protein connexin 43 was clearly observed intercellularly in isolated clusters. All of the cardiomyocytes within each cluster beat synchronously, implying that the coupling between the cells was fully developed. Additionally, the beating rates among these isolated cell clusters could be synchronized via an electrical stimulation designed to imitate that generated in a native heart. Importantly, improving the impaired heart function depends on electrical coupling between the engrafted cells and the host myocardium to ensure their synchronized beating.
Cardiac tissue engineering is of particular importance in the combination of contracting cells with a biomaterial scaffold, which serves as a cell-delivery construct, to replace cardiomyocytes (CMs) ...that are lost as a result of an infarction, to restore heart function. However, most biomaterial scaffolds are nonconductive and may delay regional conduction, potentially causing arrhythmias. In this study, a conductive CM-delivery construct that consists of a gelatin-based gelfoam that is conjugated with a self-doped conductive polymer (poly-3-amino-4-methoxybenzoic acid, PAMB) is proposed as a cardiac patch (PAMB-Gel patch) to repair an infarcted heart. A nonconductive plain gelfoam (Gel patch) is used as a control. The electrical conductivity of the PAMB-Gel patch is approximately 30 times higher than that of the Gel patch; as a result, the conductive PAMB-Gel patch can substantially increase electrical conduction between distinct clusters of beating CMs, facilitating their synchronous contraction. In vivo epicardial implantation of the PAMB-Gel patch that is seeded with CMs (the bioengineered patch) in infarcted rat hearts can significantly enhance electrical activity in the fibrotic tissue, improving electrical impulse propagation and synchronizing CM contraction across the scar region, markedly reducing its susceptibility to cardiac arrhythmias. Echocardiography shows that the bioengineered conductive patch has an important role in the restoration of cardiac function, perhaps owing to the synergistic effects of its conductive construct and the synchronously beating CMs. These experimental results reveal that the as-proposed bioengineered conductive patch has great potential for repairing injured cardiac tissues.
Implantation of the bioengineered conductive patch in infarcted hearts improves electrical impulse propagation and synchronizes cardiomyocyte contraction across the scar region, reducing susceptibility such hearts to cardiac arrhythmias and restoring heart function. Display omitted
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