A real-world pharmacovigilance analysis of the FDA adverse event reporting system events for polatuzumab vedotin.

BACKGROUND: Polatuzumab vedotin is the first antibody-drug conjugate approved by the US Food and Drug Administration (FDA) for patients with diffuse large B-cell lymphoma. This study evaluated adverse events (AEs) associated with polatuzumab vedotin by data mining of the FDA Adverse Event Reporting System (FAERS). METHODS: This study included AEs registered in FAERS between 2019 Q2 and 2023 Q2. Four algorithms were used to quantify the signals of polatuzumab vedotin-associated AEs, including reporting odds ratio, proportional reporting ratio, Bayesian confidence propagation neural network, and multi-item gamma Poisson shrinker. RESULTS: A total of 7,609,450 reports were collected from the FAERS database, and 1,388 reports of polatuzumab vedotin were identified as primary suspected AEs. Polatuzumab vedotin-associated AEs involved 26 organ systems. According to the four algorithms, 108 significant disproportionality AEs were retained simultaneously. Unexpected significant AEs included gastrointestinal hemorrhage, ileus, gastrointestinal perforation, cholecystitis, hypogammaglobulinemia, hepatitis B reactivation, hypercalcemia, hydronephrosis, cystitis hemorrhagic, interstitial lung disease, and thrombophlebitis. The median time to onset of polatuzumab vedotin-associated AEs was 20 (interquartile range 4-56) days. CONCLUSIONS: Our study identified significant new AE signals for polatuzumab vedotin through real-world disproportionality analysis data and may provide additional evidence for risk identification of polatuzumab vedotin.

Contrastive analysis on the safety of brand and generic nebivolol: a real-world pharmacovigilance study based on the FDA adverse event reporting system.

Background: The equivalence of generic drugs to their brand-name counterparts is a controversial issue. Current literature indicates disparities between the generic nebivolol (GN) and the brand nebivolol (BN). Aim: The study is designed to investigate the safety difference between GN and BN and provide reference information for clinical practice. Methods: We reviewed adverse event (AE) reports that recorded nebivolol as the primary suspect drug in the FDA Adverse Event Reporting System (FAERS) database from 2004 to 2022, conducted a disproportional analysis to detect signals for the GN and BN respectively, and compared the AE heterogeneity between them using the Breslow-Day test. Results: A total of 2613 AE reports of nebivolol were recorded in the FAERS database from 2004 to 2022, of which 2,200 were classified as BN, 346 as GN, and 67 unclassifiable AE reports were excluded. The signals of 37 AEs distributed in cardiac, gastrointestinal, psychiatric, and nervous systems were detected in disproportional analysis. 33 out of 37 AEs were positive signals, with 21 not previously listed on the drug label, indicating an unrecognized risk with nebivolol. In the heterogeneity analysis of AE signals between GN and BN, the GN generally showed a higher AE signal value than BN, especially 15 AEs distributed in the cardiac, neurological, and psychiatric systems that showed statistically significantly higher risk by taking GN. Conclusion: Our study shows some previously overlooked adverse effects of nebivolol. It suggests that the risk of GN's adverse effects may be higher than those in BN, which deserves further attention and investigation by healthcare professionals, regulators, and others.

N76-1, a novel CDK7 inhibitor, exhibits potent anti-cancer effects in triple negative breast cancer.

Emerging evidence suggests that genetically highly specific triple-negative breast cancer (TNBC) possesses a relatively uniform transcriptional program that is abnormally dependent on cyclin-dependent kinase 7 (CDK7). In this study, we obtained an inhibitor of CDK7, N76-1, by attaching the side chain of the covalent CDK7 inhibitor THZ1 to the core of the anaplastic lymphoma kinase inhibitor ceritinib. This study aimed to elucidate the role and underlying mechanism of N76-1 in TNBC and evaluate its potential value as an anti-TNBC drug. The results of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and colony formation assays showed that N76-1 inhibited the viability of TNBC cells. Kinase activity and cellular thermal shift assays showed that N76-1 directly targeted CDK7. Flow cytometry results revealed that N76-1 induced apoptosis and cell cycle arrest in the G2/M phase. N76-1 also effectively inhibited the migration of TNBC cells by high-content detection. The RNA-seq analysis showed that the transcription of genes, especially those related to transcriptional regulation and cell cycle, was suppressed after N76-1 treatment. Moreover, N76-1 markedly inhibited the growth of TNBC xenografts and phosphorylation of RNAPII in tumor tissues. In summary, N76-1 exerts potent anticancer effects in TNBC by inhibiting CDK7 and provides a new strategy and research basis for the development of new drugs for TNBC.

Nomograms for predicting overall survival in colorectal cancer patients with metastasis to the liver, lung, bone, and brain.

BACKGROUND: The aim of this study was to identify the heterogeneous and homogeneous prognostic factors associated with distant metastasis to the liver, lung, bone, and brain in colorectal cancer (CRC) patients and then construct nomograms to predict the prognosis. METHODS: CRC patients registered in the surveillance, epidemiology, and end results database between 2010 and 2017 were included. A Cox regression model was used to analyse homogeneous and heterogeneous prognostic factors, and Kaplan‒Meier analysis was performed to estimate overall survival (OS). Predictive nomograms were constructed, and their performance was evaluated with C-indexes, calibration curves and the area under the receiver operating characteristic (ROC) curve (AUC). RESULTS: A total of 37,641 patients with distant metastasis to the liver, lung, bone, and brain were included. The median survival times of patients with liver metastasis, lung metastasis, bone metastasis, and brain metastasis were 12.00 months (95% CI 11.73-12.27 months), 10.00 months (95% CI 9.60-10.41 months), 5.00 months (95% CI 4.52-5.48 months), and 3.00 months (95% CI 2.28-3.72 months), respectively. An older age, higher N stage, elevated carcinoembryonic antigen level, no surgery at the primary site and no/unknown treatment with chemotherapy were identified as homogeneous prognostic factors for the four types of metastases. The calibration curves, C-indexes and AUCs exhibited good performance for predicting the OS of patients with distant metastases to the liver, lung, bone, and brain. CONCLUSIONS: CRC patients with distant metastasis to the liver, lung, bone, and brain exhibited homogeneous and heterogeneous prognostic factors, all of which were associated with shorter survival. The nomograms showed good accuracy and may be used as tools for clinicians to predict the prognosis of CRC patients with distant metastasis.

VPS34-IN1 induces apoptosis of ER+ breast cancer cells via activating PERK/ATF4/CHOP pathway.

VPS34-IN1 is a specific selective inhibitor of Class III Phosphatidylinositol 3-kinase (PI3K) and has been shown to exhibit a significant antitumor effect in leukemia and liver cancer. In current study, we focused on the anticancer effect and potential mechanism of VPS34-IN1 in estrogen receptor positive (ER+ ) breast cancer. Our results revealed that VPS34-IN1 inhibited the viability of ER+ breast cancer cells in vitro and in vivo. Flow cytometry and western blot analyses showed that VPS34-IN1 treatment induced breast cancer cell apopotosis. Interestingly, VPS34-IN1 treatment activated protein kinase R (PKR)-like ER kinase (PERK) branch of endoplasmic reticulum (ER) stress. Furthermore, knockdown of PERK by siRNA or inhibition of PERK activity by chemical inhibitor GSK2656157 could attenuate VPS34-IN1-mediated apoptosis in ER+ breast cancer cells. Collectively, VPS34-IN1 has an antitumor effect in breast cancer, and it may result from activating PERK/ATF4/CHOP pathway of ER stress to induce cell apoptosis. These findings broaden our understanding of the anti-breast cancer effects and mechanisms of VPS34-IN1 and provide new ideas and reference directions for the treatment of ER+ breast cancer.

Celastrol targets the ChREBP-TXNIP axis to ameliorates type 2 diabetes mellitus.

BACKGROUNDS: Thioredoxin-interacting protein (TXNIP) plays a pivotal role in regulation of blood glucose homeostasis and is an emerging therapeutic target in diabetes and its complications. Celastrol, a pentacyclic triterpene extracted from the roots of Tripterygium wilfordii Hook F, can reduce insulin resistance and improve diabetic complications. PURPOSE: This study aimed to untangle the mechanism of celastrol in ameliorating type 2 diabetes (T2DM) and evaluate its potential benefits as an anti-diabetic agent. METHODS: db/db mice was used to evaluate the hypoglycemic effect of celastrol in vivo; Enzyme-linked immunosorbent assay (ELISA) and 2-NBDG assay were used to detect the effect of celastrol on insulin secretion and glucose uptake in cells; Western blotting, quantitative reverse transcription PCR (RT-qPCR) and immunohistological staining were used to examine effect of celastrol on the expression of TXNIP and the carbohydrate response element-binding protein (ChREBP). Molecular docking, cellular thermal shift assay (CETSA), drug affinity responsive targets stability assay (DARTS) and mass spectrometry were used to test the direct binding between celastrol and ChREBP. Loss- and gain-of-function studies further confirmed the role of ChREBP and TXNIP in celastrol-mediated amelioration of T2DM. RESULTS: Celastrol treatment significantly reduced blood glucose level, body weight and food intake, and improved glucose tolerance in db/db mice. Moreover, celastrol promoted insulin secretion and improved glucose homeostasis. Mechanistically, celastrol directly bound to ChREBP, a primary transcriptional factor upregulating TXNIP expression. By binding to ChREBP, celastrol inhibited its nuclear translocation and promoted its proteasomal degradation, thereby repressing TXNIP transcription and ultimately ameliorating T2DM through breaking the vicious cycle of hyperglycemia deterioration and TXNIP overexpression. CONCLUSION: Celastrol ameliorates T2DM through targeting ChREBP-TXNIP aix. Our study identified ChREBP as a new direct molecular target of celastrol and revealed a novel mechanism for celastrol-mediated amelioration of T2DM, which provides experimental evidence for its possible use in the treatment of T2DM and new insight into diabetes drug development for targeting TXNIP.

Quantitative profiling of differentially expressed oxylipins in ADSCs under proinflammatory cytokine stimulation.

Mesenchymal stem cells (MSCs) have been proved to have anti-inflammatory capabilities, but the mechanisms are still under investigation. Recently, oxylipins have been identified as being related to the immuno-regulation function of MSCs, but the MSC-derived oxylipins, especially under the stimulation of versatile pro-inflammatory cytokines, have never been comprehensively analyzed. In the present research, a UPLC-MS/MS method was employed to identify and quantify the oxylipin profiles of adipose-derived mesenchymal stem cells (ADSCs) under cytokine stimulation (IL-1ß, TNF-α, IFN-𝛾 and TNF-α + IFN-𝛾). The differentially produced oxylipins between experimental groups were analyzed and compared. The elevated level of lipoxygenase-15 (LOX-15) mRNA was further verified by qRT-PCR analysis. From the targeted 71 oxylipins, we detected and quantified 57 oxylipins, while 14 were not detected. Distinctive from other cytokines, ADSCs activated by the combination of IFN-𝛾 and TNF-α up-regulated LOX-15 products 7-HDHA and 15-HEPE, which were metabolized from docosahexaenoic acid (DHA) and eicosapentaenoic acid, respectively, and involved in the pro-resolution phase of inflammation. The results reported here make a first step towards a comprehensive characterization of MSC-derived oxylipins under differential proinflammatory cytokine stimulation. The findings may lay a fundamental foundation for MSC-based therapies and further determine ways to optimize the therapeutic potential of MSCs.

Homogeneous and heterogeneous risk and prognostic factors for lung metastasis in colorectal cancer patients.

BACKGROUND: The lung is one of the most frequent distant metastasis sites in colorectal cancer (CRC) patients; however, lung metastasis risk and prognostic factors have not been comprehensively elucidated. This study aimed to identify the homogeneous and heterogeneous lung metastasis risk and prognostic factors in CRC patients using the Surveillance, Epidemiology, and End Results (SEER) database. METHODS: CRC patients registered in the SEER database between 2010 and 2016 were included to analyse risk factors for developing lung metastasis by using univariable and multivariable logistic regression. Patients diagnosed between 2010 and 2015 were selected to investigate prognostic factors for lung metastasis by conducting Cox regression. Kaplan-Meier analysis was used to estimate overall survival outcomes. RESULTS: A total of 10,598 (5.2%) patients with synchronous lung metastasis were diagnosed among 203,138 patients with CRC. The median survival time of patients with lung metastasis was 10.0 months (95% CI 9.6-10.5 months). Older age, unmarried status, uninsured status, poor histological differentiation, more lymphatic metastasis, CEA positivity, liver metastasis, bone metastasis and brain metastasis were lung metastasis risk and prognostic factors. Black patients and those with left colon, rectum, and stage T4 disease were more likely to develop lung metastasis, while patients with right colon cancer and no surgical treatment of the primary tumour had poor survival outcomes. CONCLUSION: The incidence of lung metastasis in CRC patients was 5.2%. CRC patients with lung metastasis exhibited homogeneous and heterogeneous risk and prognostic factors. These results are helpful for clinical evaluation and individual treatment decision making.

Weighted Gene Co-Expression Network Analysis and Treatment Strategies of Tumor Recurrence-Associated Hub Genes in Lung Adenocarcinoma.

Despite the recent progress of lung adenocarcinoma (LUAD) therapy, tumor recurrence remained to be a challenging factor that impedes the effectiveness of treatment. The objective of the present study was to predict the hub genes affecting LUAD recurrence via weighted gene co-expression network analysis (WGCNA). Microarray samples from LUAD dataset of GSE32863 were analyzed, and the modules with the highest correlation to tumor recurrence were selected. Functional enrichment analysis was conducted, followed by establishment of a protein-protein interaction (PPI) network. Subsequently, hub genes were identified by overall survival analyses and further validated by evaluation of expression in both myeloid populations and tissue samples of LUAD. Gene set enrichment analysis (GSEA) was then carried out, and construction of transcription factors (TF)-hub gene and drug-hub gene interaction network was also achieved. A total of eight hub genes (ACTR3, ARPC5, RAB13, HNRNPK, PA2G4, WDR12, SRSF1, and NOP58) were finally identified to be closely correlated with LUAD recurrence. In addition, TFs that regulate hub genes have been predicted, including MYC, PML, and YY1. Finally, drugs including arsenic trioxide, cisplatin, Jinfukang, and sunitinib were mined for the treatment of the eight hub genes. In conclusion, our study may facilitate the invention of targeted therapeutic drugs and shed light on the understanding of the mechanism for LUAD recurrence.

Qihu Preparation Ameliorates Diabetes by Activating the AMPK Signaling Pathway in db/db Mice.

PURPOSE: To examine the pharmacological effects of Qihu on type 2 diabetes mellitus using db/db mice. MATERIALS AND METHODS: Thirty-seven db/db mice were randomly divided into the following 5 groups: diabetes model control group (DM group; n = 7), administered with the adjuvant 0.3% carboxymethyl cellulose-Na; positive control group (Met group; n = 8), administered with metformin (0.13 g/kg bodyweight); Qihu-L group (n = 7), administered with a low dose of Qihu (0.75 g/kg bodyweight), Qihu-M group (n = 7), administered with a medium dose of Qihu (1.5 g/kg bodyweight); Qihu-H group (n = 8), administered with a high dose of Qihu (3.0 g/kg bodyweight). BKS mice (n = 8) were used as the negative control group. The db/db mice were administered with drugs through oral gavage for 28 days. The random blood glucose levels, glucose tolerance test, bodyweight, food intake, and blood lipid levels of the mice were measured during the experimental period. The liver and pancreas tissues were collected for pathological, quantitative real-time polymerase chain reaction, and Western blotting analyses. RESULTS: Compared with the DM group, the Qihu groups exhibited decreased bodyweight gain. The blood glucose levels in the Qihu-L, Qihu-M, and Qihu-H were 31.46%, 43.73%, and 51.83%, respectively, lower than those in the DM group. The triglyceride levels were significantly downregulated and the swelling and steatosis of the hepatocytes were significantly lower in the Qihu-M and Qihu-H groups than in the DM group. Qihu downregulated the expression of IL-1ß, IL-6, and TXNIP and upregulated the AMP-activated protein kinase (AMPK) signaling pathway in the pancreas and liver tissues of db/db mice. CONCLUSION: The anti-diabetic effects of Qihu are mediated through the activation of the AMPK/Txnip signaling and the downregulation of the secretion of inflammatory factors in db/db mice.

YY1-mediated up-regulation of lncRNA LINC00466 facilitates glioma progression via miR-508/CHEK1.

BACKGROUND: The abnormal expression of lncRNA LINC00466 (LINC00466) has been demonstrated in several tumor types. However, the expression pattern and functions of LINC00466 in glioma remain uninvestigated. METHODS: A reverse transcriptase-polymerase chain reaction (RT-PCR) was utilized to analyze LINC00466 in human glioma tissues and cell lines. Luciferase reporter assays were performed to explore whether YY1 could bind to the promoter region of LINC00466. Cell counting kit-8, flow cytometry, colony-formation, transwell migration and invasion assays were carried out to determine the involvement of INC00466 in glioma. Luciferase assays and pulldown assays were conducted to verify the binding sites. RESULTS: We report that LINC00466 expression is increased in glioma cells and tissues. YY1 transcription factor (YY1) can bind directly to the LINC00466 promoter region. Clinical studies revealed that the elevated expression of LINC00466 is closely correlated with an advanced World Health Organization grade (p = 0.008), Karnofsky Performance Status score (p = 0.004) and a short overall survival (p = 0.0035) of glioma patients. Functional assays revealed that LINC00466 knockdown distinctly suppresses glioma cell proliferation, migration, invasion and epithelial-mesenchymal progress, and also promotes apoptosis. Moreover, dual-luciferase reporter assays indicated that LINC00466 acts as an endogenous sponge via binding to miR-508 and decreasing its expression. Luciferase assays and RT-PCR assays demonstrated that checkpoint kinase 1 (CHEK1) is a target of miR-508, and LINC00466 modulates CHEK1 levels by competing for miR-508. LINC00466 may exhibit its anti-oncogenic roles through targeting the miR-508/CHEK1 axis. CONCLUSIONS: Our findings identified a novel glioma-related long non-coding RNA, LINC00466, which may provide a potential novel prognostic and therapeutic target for glioma.

Enhancing and Complementary Mechanisms of Synergistic Action of Acori Tatarinowii Rhizoma and Codonopsis Radix for Alzheimer's Disease Based on Systems Pharmacology.

MATERIALS AND METHODS: In this study, a systems pharmacology-based strategy was used to elucidate the synergistic mechanism of Acori Tatarinowii Rhizoma and Codonopsis Radix for the treatment of AD. This novel systems pharmacology model consisted of component information, pharmacokinetic analysis, and pharmacological data. Additionally, the related pathways were compressed using the Kyoto Encyclopedia of Genes and Genomes (KEGG) database, and the organ distributions were determined in the BioGPS bank. RESULTS: Sixty-eight active ingredients with suitable pharmacokinetic profiles and biological activities were selected through ADME screening in silico. Based on 62 AD-related targets, such as APP, CHRM1, and PTGS1, systematic analysis showed that these two herbs were mainly involved in the PI3K-Akt signaling pathway, MAPK signaling pathway, neuroactive ligand-receptor interaction, and fluid shear stress and atherosclerosis, indicating that they had a synergistic effect on AD. However, ATR acted on the KDR gene, while CR acted on IGF1R, MET, IL1B, and CHUK, showing that they also had complementary effects on AD. The ingredient contribution score involved 29 ingredients contributing 90.14% of the total contribution score of this formula for AD treatment, which emphasized that the effective therapeutic effects of these herbs for AD were derived from both ATR and CR, not a single herb. Organ distribution showed that the targets of the active ingredients were mainly located in the whole blood, the brain, and the muscle, which are associated with AD. CONCLUSIONS: In sum, our findings suggest that the systems pharmacology methods successfully revealed the synergistic and complementary mechanisms of ATR and CR for the treatment of AD.

Meta-analysis of the adverse events associated with extended-release versus standard immediate-release pramipexole in Parkinson disease.

BACKGROUND: In order to increase treatment choices for patients with Parkinson disease (PD), we performed a retrospective assessment of adverse events associated with a novel once-daily extended-release (ER) formulation versus the standard immediate-release (IR) of the nonergolinic dopamine agonist, pramipexole. METHODS: The PubMed and Embase databases, as well as the foreign language medical information resource retrieval platform were searched from 2007 to 2017. The relative risks (RR) of various adverse events with 95% confidence intervals (95% CIs) were generated. The Modified Jadad score (MJs) was used to assess the quality of individual studies. Funnel plots were used to evaluate publication bias. RESULTS: Three randomized controlled trials involving 1021 patients were included in this meta-analysis. We evaluated common adverse events associated with pramipexole in the gastrointestinal and nervous systems. These included the typical gastrointestinal symptom of nausea (RR = 0.96, 95% CI: 0.72-1.28; P = .80 > .05) and nervous system symptoms of somnolence (RR = 1.16, 95% CI: 0.95-1.43; P = .14 > .05), dizziness (RR = 1.11, 95% CI: 0.80-1.54; P = .54 > .05), and dyskinesia (RR = 0.87, 95% CI: 0.47-1.60; P = .66 > .05). CONCLUSION: Patients with PD treated with 2 different pramipexole formulations (ER and IR) had similar incidences of common adverse events.