A real-world disproportionality analysis of semaglutide: Post-marketing pharmacovigilance data.

AIM/INTRODUCTION: The recent adverse reactions associated with semaglutide have led the Food and Drug Administration (FDA) to issue a "black box warning", and it is necessary to analyze all reports of adverse reactions to improve the safety of its clinical use. MATERIALS AND METHODS: Statistical analyses and signal mining were performed by obtaining the adverse event reports related to semaglutide in the FAERS database from the first quarter of 2018 to the fourth quarter of 2023. We used disproportionality and Bayesian analysis to examine clinical and demographic attributes, trends reported quarterly, and contrasts between two distinct indications (obesity and type 2 diabetes). RESULTS: We found 10 unexpected adverse signals related to "pancreatic cancer", "intestinal obstruction", "cholecystitis", and "polycystic ovary" and both the two different indications had the same serious adverse reaction events occurring. CONCLUSIONS: This study identified many unexpected signals of serious adverse reactions, suggesting the importance of continuous post-marketing surveillance of semaglutide to understand its potential risks.

Combined immunochemotherapy achieving targeted co-delivery of chlorogenic acid and doxorubicin by sialic acid-modified liposomes enhances anti-cancer efficacy.

Malignant melanoma is a high-grade aggressive skin tumor with an increasing incidence and mortality rates worldwide. Chemotherapeutic drugs such as doxorubicin have limited efficacy against melanoma due to their poor sensitivity, severe side effects, and drug resistance. Recent studies have shown that combinations of immunotherapy and chemotherapy have a synergistic effect in enhancing the anti-tumor effect. Here, we have developed liposomes co-loaded with chlorogenic acid (CA) and doxorubicin (DOX), modified with sialic acid-octadecylamine conjugate (SA-ODA), designated CA-DOX-SAL, that facilitate drug delivery by recognizing Siglec-1 receptor on TAMs. The physicochemical studies revealed the particle size and zeta potential of CA-DOX-SAL as 128.3 ± 0.8 nm and - 4.33 ± 0.50 mV, respectively. In vitro, CA-DOX-SAL demonstrated robust cellular uptake through SA receptor-mediated tumor-associated macrophages (TAM) targeting and exerted greater cytotoxicity on tumor cells. In vivo, targeted liposomes were found to accumulate in the tumor area, leading to an improvement in anti-tumor efficacy. In addition, CA-DOX-SAL effectively inhibited B16F10 melanoma tumor growth by stimulating the transition from tumor-promoting M2-type to anti-tumor M1-type and directly killing tumor cells. Overall, the co-delivery of immunomodulatory CA and chemotherapeutic DOX presents a promising therapeutic strategy to enhance clinical outcomes in the treatment of melanoma.

Recent progress in the applications of gold-based nanoparticles towards tumor-targeted imaging and therapy.

Cancer death rate remains high all over the world, scientists are paying increasing attention to meet the requirements for precise diagnosis and therapy. Therefore, early diagnosis and active treatment can effectively improve the five-year survival rate of patients. In recent years, gold-based nanomaterials have received increasing attention in medical fields due to their excellent biocompatibility, low toxicity and unique properties. In addition, because of the inherent nature of gold nanomaterials including for computed tomography (CT), fluorescence/optical imaging (FI/OI), surface enhanced Raman spectroscopy imaging (SERS), photoacoustic imaging (PAI) and photothermal therapy (PTT), various gold nanomaterials were developed as theranostic nanoplatforms. In this review, we summarized the latest developments of nanomaterials in imaging and combined therapy, and the prospects for the future application of gold-based theranostic nanoplatforms were also proposed.

Adsorption film with sub-milli-interface morphologies via direct ink writing for indoor formaldehyde removal.

In-situ thermally regenerated flexible adsorption films are superior for long-term purification of indoor low-concentration volatile organic compounds (VOCs). To further improve the adsorption kinetics of the films, the surface morphology of adsorption films was suggested in hierarchical channel structure. However, such structure is far from practical applications because of its complicated fabrication method and limited flexibility. In this study, we proposed a convenient and fast method named direct ink writing (DIW) based 3D printing to fabricate flexible adsorption films. Inks were prepared to have appropriate rheological properties and good printability. Three types of adsorption film (flat, straight finned, and trough-like finned) were constructed on flexible polyimide circuit substrates by DIW. We utilized the printed adsorption films for indoor level (1 ppm) formaldehyde removal. The trough-like finned film achieved the best performance among the three printed films, showing a 275% longer penetration time and 252% larger effective adsorption capacity than the flat film. By conducting a 7-cycle adsorption-desorption experiment (more than 12 h), we verified that the films' adsorption performance could effectively recover via in-situ heating. This work could dance around the complicated coating process, increase the structural flexibility and reduce the adsorbent interfacial modification cost.

Synergistic photobiomodulation with 808-nm and 1064-nm lasers to reduce the ß-amyloid neurotoxicity in the in vitro Alzheimer's disease models.

Background: In Alzheimer's disease (AD), the deposition of ß-amyloid (Aß) plaques is closely associated with the neuronal apoptosis and activation of microglia, which may result in the functional impairment of neurons through pro-inflammation and over-pruning of the neurons. Photobiomodulation (PBM) is a non-invasive therapeutic approach without any conspicuous side effect, which has shown promising attributes in the treatment of chronic brain diseases such as AD by reducing the Aß burden. However, neither the optimal parameters for PBM treatment nor its exact role in modulating the microglial functions/activities has been conclusively established yet. Methods: An inflammatory stimulation model of Alzheimer's disease (AD) was set up by activating microglia and neuroblastoma with fibrosis ß-amyloid (fAß) in a transwell insert system. SH-SY5Y neuroblastoma cells and BV2 microglial cells were irradiated with the 808- and 1,064-nm lasers, respectively (a power density of 50 mW/cm2 and a dose of 10 J/cm2) to study the PBM activity. The amount of labeled fAß phagocytosed by microglia was considered to assess the microglial phagocytosis. A PBM-induced neuroprotective study was conducted with the AD model under different laser parameters to realize the optimal condition. Microglial phenotype, microglial secretions of the pro-inflammatory and anti-inflammatory factors, and the intracellular Ca2+ levels in microglia were studied in detail to understand the structural and functional changes occurring in the microglial cells of AD model upon PBM treatment. Conclusion: A synergistic PBM effect (with the 808- and 1,064-nm lasers) effectively inhibited the fAß-induced neurotoxicity of neuroblastoma by promoting the viability of neuroblastoma and regulating the intracellular Ca2+ levels of microglia. Moreover, the downregulation of Ca2+ led to microglial polarization with an M2 phenotype, which promotes the fAß phagocytosis, and resulted in the upregulated expression of anti-inflammatory factors and downregulated expression of inflammatory factors.

On-chip rapid drug screening of leukemia cells by acoustic streaming.

Rapid and personalized single-cell drug screening testing plays an essential role in acute myeloid leukemia drug combination chemotherapy. Conventional chemotherapeutic drug screening is a time-consuming process because of the natural resistance of cell membranes to drugs, and there are still great challenges related to using technologies that change membrane permeability such as sonoporation in high-throughput and precise single-cell drug screening with minimal damage. In this study, we proposed an acoustic streaming-based non-invasive single-cell drug screening acceleration method, using high-frequency acoustic waves (>10 MHz) in a concentration gradient microfluidic device. High-frequency acoustics leads to increased difficulties in inducing cavitation and generates acoustic streaming around each single cell. Therefore, single-cell membrane permeability is non-invasively increased by the acoustic pressure and acoustic streaming-induced shear force, which significantly improves the drug uptake process. In the experiment, single human myeloid leukemia mononuclear (THP-1) cells were trapped by triangle cell traps in concentration gradient chips with different cytarabine (Ara-C) drug concentrations. Due to this dual acoustic effect, the drugs affect cell viability in less than 30 min, which is faster than traditional methods (usually more than 24 h). This dual acoustic effect-based drug delivery strategy has the potential to save time and reduce the cost of drug screening, when combined with microfluidic technology for multi-concentration drug screening. This strategy offers enormous potential for use in multiple drug screening or efficient drug combination screening in individualized/personalized treatments, which can greatly improve efficiency and reduce costs.

Tumor-associated macrophages: role in tumorigenesis and immunotherapy implications.

Tumor-associated macrophages (TAMs) occupy an important position in the tumor microenvironment (TME), they are a highly plastic heterogeneous population with complex effects on tumorigenesis and development. TAMs secrete a variety of cytokines, chemokines, and proteases, which promote the remodeling of extracellular matrix, tumor cell growth and metastasis, tumor vessel and lymphangiogenesis, and immunosuppression. TAMs with different phenotypes have different effects on tumor proliferation and metastasis. TAMs act a pivotal part in occurrence and development of tumors, and are very attractive target to inhibit tumor growth and metastasis in tumor immunotherapy. This article reviews the interrelationship between TAMs and tumor microenvironment and its related applications in tumor therapy.

Anti-leukemia activities of selenium nanoparticles embedded in nanotube consisted of triple-helix ß-d-glucan.

Acute myeloid leukemia (AML) is a difficult therapeutic hematological tumor. It is urgent to find a non-toxic natural drug to treat AML. Herein, the selenium nanoparticles (SeNPs) embedded in nanotubes consisted of triple helix ß-(1, 3)-d-glucan (BFP) from the black fungus that were wrapped to form stable inclusion complex BFP-Se, which was self-assembled and exhibited high stability in water. In vitro, the BFP-Se significantly inhibited the proliferation of AML cells and increased the cytotoxicity on AML cells. On single-cell levels, the U937 cells were gradually swelled and lysed with BFP-Se treatment on optofluidics chips. Further, the blood and bone marrow analysis indicated the anti-leukemia effects of BFP-Se in vivo. Moreover, BFP-Se increased the total antioxidant capacity of AML cells and decreased the expression of c-Jun activation domain-binding protein 1 and thioredoxin 1. Our results suggest that this biocompatible polysaccharide nanotube containing Se nanoparticles would provide a novel strategy for AML therapy.

Establishing a prediction model of infection during the intravesical instillation of bladder cancer: a multicenter retrospective study.

Objective: To explore the independent risk factors of infection during the intravesical instillation of bladder cancer and establish a prediction model, which may reduce probability of infection for bladder cancer patients. Material and Methods: 533 patients with newly discovered NMIBC at two hospitals from January 2017 to December 2019 were enrolled in this study. The patients were divided into "infection positive group" and "infection negative group". The clinical data of the two groups were analyzed by logistic regression analyses. Nomogram was generated and ROC curve, calibration curve were structured to assess the accuracy of nomogram. An independent cohort included 174 patients from another hospital validated the nomogram prediction model. Results: Of 533 patients, 185 patients had an infection. Univariate and multivariate logistic regression analyses showed diabetes mellitus, hemiplegia, patients without antibiotics and perfusion frequency (≥2 times/month) were the independent risk factors. AUC of the ROC was 0.858 (0.762-0.904). The nomogram could predict the probability of infection during the intravesical instillation of bladder tumor calibration curve showed good agreement. The external data validation gained good sensitivity and specificity, which indicated that the nomogram had great value of prediction. Conclusions: Individualized prediction of the probability of infection may reduce the incidence of infection by argeted preventive measures.

On-chip hydrogel arrays individually encapsulating acoustic formed multicellular aggregates for high throughput drug testing.

Multicellular aggregates in three-dimensional (3D) environments provide novel solid tumor models that can provide insight into in vivo drug resistance. Such models are therefore essential for developing new drugs and preventing the failure of clinical treatments. However, high-throughput cell cluster assembly and fabricating individual 3D environments that mimic the extracellular matrix (ECM) remain significant challenges. To rapidly produce mini 3D multicellular aggregate units, acoustic force assembly combined with ECM mimic hydrogel array encapsulation is developed and then integrated into a diffusion-based microfluidic device for high-throughput drug testing. The active acoustic force gathers human mononuclear leukemia cells (THP-1) into hundreds of multicellular clusters with a controllable size. Instead of continuous bulk materials, photosensitive gelatin methacryloyl (GelMA) hydrogel pillar arrays containing cell clusters at drug concentration gradients are obtained through selective area exposure. Ten azelaic acid (AZA) concentration gradient series are applied to 100 units to simultaneously test the multicellular cluster drug resistance to multiple drug conditions. Real-time green fluorescent protein (GFP) fluorescence is analyzed to monitor cell viability. The results show that cell aggregate activity is inversely related to the drug concentration in the hydrogel pillars, and shows lower sensitivity to drug toxicity than the activity of monolayer cultured cells. The 3D multicellular arrays provide numerous in vitro tumor models and can be directly used for downstream drug testing. This technology inherits the advantages of acoustic assembly, while being more flexible, practical, and high-throughput, and shows significant potential for use in further tumor related research and clinical practice.

All-in-one mitochondria-targeted NIR-II fluorophores for cancer therapy and imaging.

Small-molecule subcellular organelle-targeting theranostic probes are crucial for early disease diagnosis and treatment. The imaging window of these molecules is mainly focused on the visible and near-infrared region (below ∼900 nm) which limits the tissue penetration depth and therapeutic effects. Herein, a novel NIR-II small-molecule probe H4-PEG-Glu with a thiopyrylium cation was synthesized. H4-PEG-Glu not only can quickly and effectively image mitochondria in acute myeloid leukemia (AML) cells, and induce G0/G1 phase arrest by the intrinsic mitochondrial apoptosis pathway w/o irradiation, but also exhibit moderate cytotoxicity against AML cancer cells in a dose dependent-manner without laser irradiation. The THP-1 cells treated with H4-PEG-Glu upon NIR laser irradiation showed enhanced chemo- and photothermal therapy (CPTT) with 93.07% ± 6.43 apoptosis by Annexin V staining. Meanwhile, H4-PEG-Glu displayed high synergistic CPTT effects in vivo, as well as specific NIR-II tumor imaging in AML patient derived PDX mouse models for the first time. Our work lays down a solid foundation for designing small-molecule NIR-II mitochondria-selective theranostic probes.

Azelaic Acid Exerts Antileukemia Effects against Acute Myeloid Leukemia by Regulating the Prdxs/ROS Signaling Pathway.

Acute myeloid leukemia (AML) is a hematological malignancy with a poor prognosis attributed to elevated reactive oxygen species (ROS) levels. Thus, agents that inhibit ROS generation in AML should be exploited. Azelaic acid (AZA), a small molecular compound, can scavenge ROS and other free radicals, exerting antitumor effects on various tumor cells. Herein, this study evaluated the antileukemic activity of AZA against AML via regulation of the ROS signaling pathway. We found that AZA reduced intracellular ROS levels and increased total antioxidant capacity in AML cell lines and AML patient cells. AZA suppressed the proliferation of AML cell lines and AML patient cells, expending minimal cytotoxicity on healthy cells. Laser confocal microscopy showed that AZA-treated AML cells surged and ruptured gradually on microfluidic chips. Additionally, AZA promoted AML cell apoptosis and arrested the cell cycle at the G1 phase. Further analysis demonstrated that peroxiredoxin (Prdx) 2 and Prdx3 were upregulated in AZA-treated AML cells. In vivo, AZA prolonged survival and attenuated AML by decreasing CD33+ immunophenotyping in the bone marrow of a patient-derived xenograft AML model. Furthermore, mice in the AZA-treated group had an increased antioxidant capacity and Prdx2/Prdx3 upregulation. The findings indicate that AZA may be a potential agent against AML by regulating the Prdxs/ROS signaling pathway.

The novel thioredoxin reductase inhibitor A-Z2 triggers intrinsic apoptosis and shows efficacy in the treatment of acute myeloid leukemia.

Chemoresistance and high incidence of relapse in acute myeloid leukemia (AML) patients are associated with thioredoxin (Trx) overexpression. Thus, targeting the Trx system has emerged as a promising approach to treating AML. Both arsenicals and azelaic acid (AZA) are thioredoxin reductase (TrxR) inhibitors and possess antileukemic effects. In this study, to exploit agents with higher potency and lower toxicity, we got some organic arsenicals and further synthesized a series of targeted compounds by binding AZA to organic arsenicals, and then screened the most effective one, N-(4-(1, 3, 2-dithiarsinan-2-yl) phenyl)-azelamide (A-Z2). A-Z2 showed a stronger inhibitory effect against TrxR activity and in AML cell lines than did AZA or arsenicals. Additionally, A-Z2 was less toxic to healthy cells compared with traditional chemotherapeutic drugs. A-Z2 induces apoptosis by collapsing of mitochondrial membrane potential, reducing ATP level, releasing of cytochrome c and TNF-α, activating of caspase 9, 8 and 3. Analysis of the mechanism revealed that A-Z2 activates the intrinsic apoptotic pathway by directly selectively targeting TrxR/Trx and indirectly inhibiting NF-κB. A-Z2's better efficacy and safety profile against arsenicals and azelaic acid were also evident in vivo. A-Z2 had better plasma stability and biological activity in rats. A-Z2-treated mice displayed significant symptom relief and prolonged survival in a patient-derived xenograft (PDX) AML model. Herein, our study provides a novel antitumor candidate and approach for treating AML.

Antiproliferative and Immunoregulatory Effects of Azelaic Acid Against Acute Myeloid Leukemia via the Activation of Notch Signaling Pathway.

Acute myeloid leukemia (AML) is a common type of hematological malignancy that can progress rapidly. AML has a poor prognosis and a high incidence of relapse due to therapeutic resistance. Azelaic acid (AZA), a small molecular compound is known to exhibit antitumor effect on various tumor cells. This study aimed to evaluate the antiproliferative and immunoregulatory effects of AZA against AMLviathe activation of the notch signaling pathway. We found that AZA can inhibit the proliferation of AML cells. In addition, laser confocal microscopy showed AZA-treated AML cells began to swelling and undergo cytoplasmic vacuolization. Importantly, AZA promoted the proliferation of NK and T cells and increased the secretion of TNF-αand IFN-γ. AZA also increased the expression levels of CD107a and TRAIL in NK cells, and CD25 and CD69 in T cells to influence their activation and cytotoxic ability. AZA-treated NK cells can kill AML cells more efficiently at the single-cell level as observed under the microfluidic chips. Further mechanistic analysis using protein mass spectrometry analysis and Notch signaling reporter assay demonstrated that Notch1and Notch2 were up-regulated and the Notch signaling pathway was activated. Moreover, combining AZA with the Notch inhibitor, RO4929097, decreased the expression of Notch1and Notch2, and downstream HES1 and HEY1, which rendered AML cells insensitive to AZA-induced apoptosis and alleviated AZA-mediated cytotoxicity in AML. In vivo, AZA relieved the leukemic spleen infiltration and extended the survival. The percentage of CD3-CD56+NK cells and CD4+CD8+T cells as well as the secretion of cytotoxic cytokines was increased after the treatment of AZA. The overall findings reveal that AZA is a potential Notch agonist against AML in activating the Notch signaling pathway.