Biomimetic Nanoplatform for Dual-Targeted Clearance of Activated and Senescent Cancer-Associated Fibroblasts to Improve Radiation Resistance in Breast Cancer.

Radiation resistance in breast cancer resulting in residual lesions or recurrence is a significant cause to radiotherapy failure. Cancer-associated fibroblasts (CAFs) and radiotherapy-induced senescent CAFs can further lead to radiation resistance and tumor immunosuppressive microenvironment. Here, an engineering cancer-cell-biomimetic nanoplatform is constructed for dual-targeted clearance of CAFs as well as senescent CAFs. The nanoplatform is prepared by 4T1 cell membrane vesicles chimerized with FAP single-chain fragment variable as the biomimetic shell for targeting of CAFs and senescent CAFs, and PLGA nanoparticles (NPs) co-encapsulated with nintedanib and ABT-263 as the core for clearance of CAFs and senescent CAFs, which are noted as FAP-CAR-CM@PLGA-AB NPs. It is evidenced that FAP-CAR-CM@PLGA-AB NPs directly suppressed the tumor-promoting effect of senescent CAFs. It also exhibits prolonged blood circulation and enhanced tumor accumulation, dual-cleared CAFs and senescent CAFs, improved radiation resistance in both acquired and patient-derived radioresistant tumor cells, and effective antitumor effect with the tumor suppression rate of 86.7%. In addition, FAP-CAR-CM@PLGA-AB NPs reverse the tumor immunosuppressive microenvironment and enhance systemic antitumor immunity. The biomimetic system for dual-targeted clearance of CAFs and senescent CAFs provides a potential strategy for enhancing the radio-sensitization of breast cancer.

Treg-Derived Extracellular Vesicles: Roles in Diseases and Theranostics.

Regulatory T cells (Tregs), a subset of CD4+ T cells, are indispensable in maintaining immune self-tolerance and have been utilized in various diseases. Treg-derived extracellular vesicles (Treg-EVs) have been discovered to play an important role in the mechanism of Treg functions. As cell-derived membranous particles, EVs carry multiple bioactive substances that possess tremendous potential for theranostics. Treg-EVs are involved in numerous physiological and pathological processes, carrying proteins and miRNAs inherited from the parental cells. To comprehensively understand the function of Treg-EVs, here we reviewed the classification of Treg-EVs, the active molecules in Treg-EVs, their various applications in diseases, and the existing challenges for Treg-EVs based theranostics. This Review aims to clarify the feasibility and potential of Treg-EVs in diseases and theranostics, facilitating further research and application of Treg-EVs.

Hypertension associated with niraparib in cancer patients: A pharmacovigilance analysis based on the FAERS database and meta-analysis of randomized controlled trials.

BACKGROUND: Niraparib plays a crucial role in the treatment of ovarian cancer. A comprehensive understanding of the incidence and risk of hypertension associated with niraparib would be of vital importance to healthcare practitioners. METHODS: In this study, an observational, retrospective, pharmacovigilance study was conducted based on the FDA Adverse Event Reporting System (FAERS) database. Cases of hypertension related to niraparib were extracted for disproportionality analysis from the first quarter (Q1) of 2017 to Q1 of 2023. Moreover, a separate meta-analysis was performed using the randomized controlled trials (RCTs) on niraparib for cancer treatment published in PubMed, Embase, and Web of Science from inception to May 31st, 2023. The primary outcomes were the incidence and risk of hypertension associated with niraparib. RESULTS: In the FAERS, 1196 hypertension cases were found to be related to niraparib treatment. Notably, niraparib exhibited the highest level of disproportionality, as indicated by a reporting odds ratio (ROR) of 2.85 (95% CI, 2.69-3.01), suggesting a greater likelihood of causing hypertension compared to other poly-ADP-ribose polymerase (PARP) inhibitors (P < 0.01). Our safety meta-analysis included five pivotal RCTs of niraparib that reported hypertension. In comparison to placebo treatment, the meta-analysis demonstrated a significant increase in the risk of hypertension with niraparib (OR 2.84 [95% CI, 2.17-3.72], P < 0.01), with no heterogeneity observed among the studies (I2 = 0%, χ2 = 2.02, P = 0.73). The incidence of niraparib-induced hypertension was determined to be 16.9% (95% CI, 14.9-18.9; I2 = 34%). CONCLUSIONS: These findings suggest that hypertension is a distinctive adverse event associated with niraparib compared to other PARP inhibitors. Niraparib significantly increases the risk of hypertension that needs early recognition and management in clinical medication.

Lipocalin 2 (LCN2) confers acquired resistance to almonertinib in NSCLC through LCN2-MMP-9 signaling pathway.

Almonertinib, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, is highly selective for EGFR-activating mutations as well as the EGFR T790M mutation in patients with advanced non-small cell lung cancer (NSCLC). However, the development of resistance inevitably occurs and poses a major obstacle to the clinical efficacy of almonertinib. Therefore, a clear understanding of the mechanism is of great significance to overcome drug resistance to almonertinib in the future. In this study, NCI-H1975 cell lines resistant to almonertinib (NCI-H1975 AR) were developed by concentration-increasing induction and were employed for clarification of underlying mechanisms of acquired resistance. Through RNA-seq analysis, the HIF-1 and TGF-ß signaling pathways were significantly enriched by gene set enrichment analysis. Lipocalin-2 (LCN2), as the core node in these two signaling pathways, were found to be positively correlated to almonertinib-resistance in NSCLC cells. The function of LCN2 in the drug resistance of almonertinib was investigated through knockdown and overexpression assays in vitro and in vivo. Moreover, matrix metalloproteinases-9 (MMP-9) was further identified as a critical downstream effector of LCN2 signaling, which is regulated via the LCN2-MMP-9 axis. Pharmacological inhibition of MMP-9 could overcome resistance to almonertinib, as evidenced in both in vitro and in vivo models. Our findings suggest that LCN2 was a crucial regulator for conferring almonertinib-resistance in NSCLC and demonstrate the potential utility of targeting the LCN2-MMP-9 axis for clinical treatment of almonertinib-resistant lung adenocarcinoma.

Incidence and risk of fatal adverse events in cancer patients treated with HER2-targeted antibody-drug conjugates: a systematic review and meta-analysis of randomized controlled trials.

OBJECTIVE: Antibody-drug conjugates (ADCs) that target human epidermal growth factor receptor 2 (HER2) are leading a new era of targeted cancer therapy. These drugs have also been associated with several fatal adverse events, such as pneumonia, interstitial lung disease, and infection. We performed a meta-analysis of randomized controlled trials (RCTs) to estimate the incidence and risk of fatal adverse events in cancer patients treated with HER2-targeted ADCs. METHODS: We performed a systematic search in Embase, PubMed, Web of Science, and Scopus databases from inception to February 1, 2022, and the last search was updated to July 1, 2023. The eligible studies for inclusion in our analysis were limited to RCTs of HER2-targeted ADCs that were approved by the US Food and Drug Administration and examined on cancer patients with available data on fatal adverse events. The protocol for this study was registered in PROSPERO (No. CRD42022331627). RESULTS: Fifteen studies (13 RCTs) involving 7,277 patients were finally included for meta-analysis. Of these patients, 4,246 received HER2-targeted ADCs and 3,481 received the control treatment. The data were combined using Bayesian hierarchical modeling, which allowed for the estimation of the mean incidence of fatal adverse events to be 0.78% (95% CrI: 0.28-1.37%, τ = 0.006) for the patients treated with HER2-targeted ADCs. The relative risk was 0.80 (95% CrI, 0.5-1.26, τ = 0.17) compared to control patients. Among 43 reported deaths caused by HER2-targeted ADCs, the most common fatal adverse event was respiratory toxicity, including pneumonia, pneumonitis, and interstitial lung disease. On subgroup analysis, no difference in the risk of fatal adverse events was found between different HER2-targeted ADCs or cancer types. CONCLUSION: Our findings suggest that the risk of fatal adverse events with HER2-targeted ADCs may be lower compared to standard control therapies in cancer patients, and there is no significant difference in risk observed between different HER2-targeted ADCs or cancer types. However, the most common fatal adverse event was respiratory toxicity, suggesting that cancer patients who use the above drugs should strengthen respiratory system monitoring and take preventive measures in some severe cases.

Dendritic cell hybrid nanovaccine for mild heat inspired cancer immunotherapy.

Cancer therapeutic vaccine can induce antigen-specific immune response, which has shown great potential in cancer immunotherapy. As the key factor of vaccine, antigen plays a central role in eliciting antitumor immunity. However, the insufficient antigen delivery and low efficiency of antigen presentation by dendritic cells (DCs) have greatly restricted the therapeutic efficiency of vaccine. Here we developed a kind of DC hybrid zinc phosphate nanoparticles to co-deliver antigenic peptide and photosensitive melanin. Owing to the chelating ability of Zn2+, the nanoparticles can co-encapsulate antigenic peptide and melanin with high efficiency. The nanovaccine showed good physiological stability with the hydration particle size was approximately 30 nm, and zeta potential was around - 10 mV. The nanovaccine showed homologous targeting effect to DCs in vivo and in vitro, efficiently delivering antigen to DCs. Meanwhile, the nanovaccine could effectively reflux to the tumor-draining lymph nodes. When combined with near-infrared irradiation, the nanovaccine induced effective mild heat in vitro and in vivo to promote antigen presentation. After administrating to MC38 tumor-bearing mice, the hybrid nanovaccine effectively promoted the maturation of DCs, the expansion of cytotoxic T lymphocytes and helper T cells, and the secretion of immunostimulatory cytokines, thereby significantly inhibiting tumor growth.

Prophylactic transanal drainage tube placement for preventing anastomotic leakage after anterior resection for rectal cancer: A meta-analysis.

AIM: The aim was to evaluate the efficacy of transanal drainage tube (TDT) placement for preventing anastomotic leakage after low anterior resection for rectal cancer. METHOD: PubMed, the Cochrane Central Register of Controlled Trials, Embase and ClinicalTrials.gov databases were searched up to October 2021. Studies comparing outcomes following low anterior resection with or without TDT were included. The primary outcomes measured were anastomotic leakage rate, reoperation rate and anastomotic bleed rate. RESULTS: Three randomized controlled trials (RCTs) and 16 observational studies (prospective or retrospective) involving 4560 patients satisfied the basic inclusion criteria. In RCTs, a TDT was associated with no statistically significant differences in anastomotic leakage (OR = 0.67, 95% CI 0.42-1.05, P = 0.08), reduction in reoperation (OR = 0.11, 95% CI 0.03-0.51, P = 0.004) and increased anastomotic bleeding rate (OR = 2.36, 95% CI 1.11-5.01, P = 0.03). In observational studies, a TDT was associated with significant reduction in anastomotic leak (OR = 0.44, 95% CI 0.30-0.64, P < 0.0001) and reoperation (OR = 0.47, 95% CI 0.33-0.69, P < 0.0001), with no statistically significant differences in anastomotic bleeding (OR = 1.30, 95% CI 0.20-8.30, P = 0.78). CONCLUSION: In RCTs, a TDT for rectal cancer was correlated with no detectable differences in anastomotic leakage and with an increased risk of anastomotic bleeding. In observational studies, a TDT was correlated with reduction in anastomotic leakage and no detectable differences in anastomotic bleeding. Both RCTs and observational studies demonstrated a comparable reduction in reoperation rate with TDT. These data in aggregate indicated that TDTs may not show superiority but emphasized differences between RCT and observational data.

Timosaponin derivative YY-23 acts as a non-competitive NMDA receptor antagonist and exerts a rapid antidepressant-like effect in mice.

AIM: N-methyl-D-aspartic acid (NMDA) receptor modulators have shown promising results as potential antidepressant agents, whereas timosaponins extracted from the Chinese herb Rhizoma Anemarrhenae exhibit antidepressant activities. In the present study we examined whether YY-23, a modified metabolite of timosaponin B-III, could affect NMDA receptors in rat hippocampal neurons in vitro, and evaluated its antidepressant-like effects in stressed mice. METHODS: NMDA-induced currents were recorded in acutely dissociated rat hippocampal CA1 neurons using a whole-cell recording technique. C57BL/6 mice were exposed to a 6-week chronic mild stress (CMS) or a 10-d chronic social defeat stress (CSDS). The stressed mice were treated with YY-23 (20 mg·kg(-1)·d(-1)) or a positive-control drug, fluoxetine (10 mg·kg(-1)·d(-1)) for 3 weeks. Behavioral assessments were carried out every week. RESULTS: In acutely dissociated rat hippocampal CA1 neurons, YY-23 selectively and reversibly inhibited NMDA-induced currents with an EC50 value of 2.8 µmol/L. This inhibition of NMDA-induced currents by YY-23 was non-competitive, and had no features of voltage-dependency or use-dependency. Treatment of the stressed mice with YY-23 not only reversed CMS-induced deficiency of sucrose preference and immobility time, and CSDS-induced reduction of social interaction, but also had faster onset as compared to fluoxetine. CONCLUSION: YY-23 is a novel non-competitive antagonist of NMDA receptors with promising rapid antidepressant-like effects in mouse models of CMS and CSDS depression.

Burst-firing patterns in the prefrontal cortex underlying the neuronal mechanisms of depression probed by antidepressants.

Major depressive disorder (MDD) is one of the leading causes of morbidity worldwide. Several antidepressants have been widely prescribed to treat patients with MDD. However, neuronal changes in brain function remain poorly understood. Based on the standard chronic mild stress (CMS) model of depression in mice, we investigated the neuronal mechanisms of the classic antidepressant, fluoxetine, and a new compound (termed YY-23 in this study) derived from furostanol saponin. The results showed that both fluoxetine and YY-23 normalized CMS-induced depressive-like behaviors. YY-23 caused antidepressant-like behaviors with a faster action than fluoxetine. In terms of in vivo neuronal activities, a CMS-induced decrease in spontaneous firing in burst of medial prefrontal cortex pyramidal neurons rather than ventral tegmental area (VTA) was reversed by the chronic administration of fluoxetine and YY-23. We also found that CMS-induced deficits in the expression of prefrontal brain-derived neurotrophic factor (BDNF) were also restored by chronically administering YY-23 and fluoxetine. In addition, chronic administration of fluoxetine rather than YY-23 resulted in an improvement of antidepressive-like behavior and a change of burst firing of VTA in control-housed animals, indicating that the pharmacological effects of YY-23 were specific to CMS-treated animals. Together, these data suggest that the burst-firing patterns of pyramidal cells may be a neural biomarker of depressive-like mice and antidepressant action. Furthermore, synaptic transmission and BDNF may contribute to the rapid antidepressant-like effects on depression.

HPLC-Q-TOF-MS/MS for analysis of major chemical constituents of Yinchen-Zhizi herb pair extract.

The Yinchen-Zhizi herb pair (YZHP) consists of Herba Artemisiae Scopariae (Yinchen in Chinese) and Fructus Gardeniae (Zhizi in Chinese), and is mainly used to treat icteric hepatitis, itching skin and eczema. However, the bioactive constituents responsible for the pharmacological effects of YZHP are still unclear to date. In this work, a rapid and sensitive method was established to comprehensively study the constituents in YZHP extract by HPLC-Q-TOF MS/MS. The analysis was performed on an HPLC system equipped with an Agilent poroshell 120 EC-C18 column (100 × 2.1 mm, 2.7 mm) working in a gradient elution program coupled to quadrupole-time-of-flight mass spectrometry operating in the negative ion mode. As a result, a total of 46 compounds including 17 from Herba Artemisiae Scopariae and 36 from Fructus Gardeniae were detected and tentatively identified in YZHP extract by comparing the retention time and mass spectrometry and retrieving the reference literature. More importantly, a series of constituents, such as many iridoid glycosides, were reported for the first time in this formula. The HPLC-Q-TOF MS/MS method was developed and utilized successfully to identify the major constituents in YZHP extract and would be helpful for further metabolism and pharmacology research on YZHP.

Fragmentation patterns study of iridoid glycosides in Fructus Gardeniae by HPLC-Q/TOF-MS/MS.

Iridoid glycosides (IGs), the major constituents in Fructus Gardeniae, have demonstrated various pharmacological activities, but there is no systematic chemical profile of IGs in Fructus Gardeniae in the published literature until now. Therefore, it is imperative that a rapid and sensitive high-performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry (HPLC-Q/TOF-MS/MS) method is established for comprehensive characterization of IGs in Fructus Gardeniae. Firstly, the fragmentation patterns of six known IGs were investigated and proposed and further concluded the diagnostic fragment ions and characteristic fragmentation pathways. Then, based on the summarized fragmentation patterns and the known compounds in the literatures, the other IGs in Fructus Gardeniae were identified successively. As a result, a total of 20 IGs were identified, of which three pairs of epimers were structurally characterized and differentiated. More importantly, one compound, the isoshanzhiside methyl ester, was tentatively identified as a new compound. The results of this study demonstrate the superiority of HPLC-MS with a high-resolution mass spectrometer for the rapid and sensitive structural elucidation of the multiple groups of constituents in Fructus Gardeniae.

Psychiatric adverse events associated with GLP-1 receptor agonists: a real-world pharmacovigilance study based on the FDA Adverse Event Reporting System database.

Background: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are widely used due to their profound efficacy in glycemic control and weight management. Within real-world contexts, the manifestation of certain psychiatric adverse events (AEs) has been observed, which is potentially linked to the administration of GLP-1 RAs. The objective of this study was to undertake a comprehensive investigation and characterization of the psychiatric AEs associated with GLP-1 RAs. Methods: We retrieved reports of AEs associated with treatment with GLP-1 RAs during the period from the first quarter (Q1) of 2004 to Q1 2023 from the FDA Adverse Event Reporting System (FAERS) database. Descriptive analysis was performed to examine the clinical characteristics and time to onset of the psychiatric AEs caused by GLP-1 RAs. Moreover, disproportionality analyses were performed using the reporting odds ratio (ROR) to identify GLP-1 RA-related psychiatric AEs. Results: A total of 8,240 reports of psychiatric AEs were analyzed out of 181,238 AE reports with treatment with GLP-1 RAs. Among these cases, a higher percentage was represented by women compared to men (65.89% vs. 30.96%). The median age of these patients was 56 years, with an interquartile range (IQR) of 48-67 years, based on data available in 286 case reports. This study showed that the median time to onset of the overall GLP-1 RA-related AEs was 31 days (IQR = 7-145.4 days), which varied among GLP-1 RA regimens. Specifically, exenatide had a significantly longer onset time at 45 days (IQR = 11-213 days), with statistically significant differences from the onset times of the other five GLP-1 RAs (p< 0.0001). Moreover, eight categories of psychiatric AEs, namely, nervousness (ROR = 1.97, 95% CI = 1.85-2.11), stress (ROR = 1.28, 95% CI = 1.19-1.38), eating disorder (ROR = 1.57, 95% CI = 1.40-1.77), fear of injection (ROR = 1.96, 95% CI = 1.60-2.40), sleep disorder due to general medical condition-insomnia type (ROR = 2.01, 95% CI = 1.60-2.52), binge eating (ROR = 2.70, 95% CI = 1.75-4.16), fear of eating (ROR 3.35, 95% CI = 1.65-6.78), and self-induced vomiting (ROR = 3.77, 95% CI = 1.77-8.03), were defined as GLP-1 RA-related psychiatric AEs through disproportionality analysis. Conclusion: Our findings demonstrate a significant association between GLP-1 RAs and the development of specific psychiatric AEs. Despite the observational nature of this pharmacovigilance study and the inherent limitations of the FAERS database, our preliminary findings in this work could provide a better basis for understanding the potential psychiatric AEs that may occur with GLP-1 RA treatment, assisting clinicians to focus on these AEs and provide early intervention for optimal risk management.

Differences in ocular adverse events associated with phosphodiesterase-5 inhibitors: a real-world pharmacovigilance study.

OBJECTIVE: Our study aims to characterize the ocular safety profiles of phosphodiesterase type 5 (PDE5) inhibitors and explore the differences among different PDE5 inhibitors. METHODS: We analyzed reports on ocular adverse events associated with sildenafil, vardenafil and tadalafil submitted to the FDA Adverse Event Reporting System (FAERS) database from the first quarter of 2004 to the first quarter of 2023. Disproportionality analysis was conducted to evaluate reporting risk profiles. RESULTS: Among 61,211 reports qualifying for analysis, 5,127 involved sildenafil, 832 vardenafil, and 3,733 tadalafil. All PDE5 inhibitors showed increased reporting odds ratios (ROR) for ocular adverse events, with vardenafil highest (ROR 4.47) followed by sildenafil and tadalafil. Key ocular adverse events included cyanopsia, optic ischemic neuropathy, visual field defects, unilateral blindness and blindness. Sildenafil showed the highest disproportionality for cyanopsia (ROR 1148.11) while vardenafil and tadalafil showed the highest disproportionality for optic ischemic neuropathy. Time-to-onset analysis also revealed significant differences, with sildenafil having a later median time-to-onset compared to vardenafil and tadalafil. CONCLUSIONS: This comprehensive pharmacovigilance study reveals distinct patterns of ocular adverse events associated with PDE5 inhibitors. These findings contribute to a better understanding of the safety profiles of PDE5 inhibitors and may guide healthcare professionals in clinical decision-making.

Hepatitis-related adverse events associated with immune checkpoint inhibitors in cancer patients: an observational, retrospective, pharmacovigilance study using the FAERS database.

Background: Immune checkpoint inhibitors (ICIs), including anti-PD-1, anti-PD-L1 and anti-CTLA-4 antibodies, have become a standard treatment for multiple cancer types. However, ICIs can induce immune-related adverse events, with hepatitis-related adverse events (HRAEs) being of particular concern. Our objective is to identify and characterize HRAEs that exhibit a significant association with ICIs using real-world data. Methods: In this observational and retrospective pharmacovigilance study, we extracted real-world adverse events reports from the FDA Adverse Event Reporting System database spanning from the first quarter of 2004 to the first quarter of 2023. We conducted both Frequentist and Bayesian methodologies in the framework of disproportionality analysis, which included the reporting odds ratios (ROR) and information components (IC) to explore the intricate relationship between ICIs and HRAEs. Results: Through disproportionality analysis, we identified three categories of HRAEs as being significantly related with ICIs, including autoimmune hepatitis (634 cases, ROR 19.34 [95% CI 17.80-21.02]; IC025 2.43), immune-mediated hepatitis (546 cases, ROR 217.24 [189.95-248.45]; IC025 4.75), and hepatitis fulminant (80 cases, ROR 4.56 [3.65-5.70]; IC025 0.49). The median age of patients who report ICI-related HRAEs was 63 years (interquartile range [IQR] 53.8-72), with a fatal outcome observed in 24.9% (313/1,260) of these reports. Cases pertaining to skin cancer, lung cancer, and kidney cancer constituted the majority of these occurrences. Patients treated with anti-PD-1 or anti-PD-L1 antibodies exhibited a higher frequency of immune-mediated hepatitis in comparison to those undergoing anti-CTLA-4 monotherapy, with a ROR of 3.59 (95% CI 1.78-6.18). Moreover, the dual ICI therapy demonstrated higher reporting rates of ICI-related HRAEs compared to ICI monotherapy. Conclusion: Our findings confirm that ICI treatment carries a significant risk of severe HRAEs, in particular autoimmune hepatitis, immune-mediated hepatitis, and hepatitis fulminant. Healthcare providers should exercise heightened vigilance regarding these risks when managing patients receiving ICIs.

Pulmonary haemorrhage and haemoptysis associated with bevacizumab-related treatment regimens: a retrospective, pharmacovigilance study using the FAERS database.

Background: Bevacizumab (BV) is widely used in routine cancer treatment and clinical therapy in combination with many other agents. This study aims to describe and analyse post-market cases of pulmonary haemorrhage and haemoptysis reported with different BV treatment regimens by mining data from the United States Food and Drug Administration Adverse Event Reporting System (FAERS) database. Methods: Data were collected from the FAERS database between 2004 Q1 and 2023 Q1. Disproportionality analysis including the reporting odds ratio (ROR) was employed to quantify the signals of disproportionate reporting of pulmonary haemorrhage and haemoptysis adverse events (AEs) associated with BV-related treatment regimens. The demographic characteristics, time to onset and outcomes were further clarified. Results: A total of 55,184 BV-associated reports were extracted from the FAERS database, of which 497 reports related to pulmonary haemorrhage and haemoptysis. Overall, the median onset time of pulmonary haemorrhage and haemoptysis AEs was 43 days (interquartile range (IQR) 15-117 days). In the subgroup analysis, BV plus targeted therapy had the longest median onset time of 90.5 days (IQR 34-178.5 days), while BV plus chemotherapy had the shortest of 40.5 days (IQR 14-90.25). BV plus chemotherapy disproportionately reported the highest percentage of death (148 deaths out of 292 cases, 50.68%). Moreover, the BV-related treatments including four subgroups in our study demonstrated the positive signals with the association of disproportionate reporting of pulmonary haemorrhage and haemoptysis. Notably, BV plus chemotherapy showed a significant higher reporting risk in pulmonary haemorrhage and haemoptysis signals of disproportionate reporting in comparison to BV monotherapy (ROR 5.35 [95% CI, 4.78-6.02] vs. ROR 4.19 [95% CI, 3.56-4.91], p = 0.0147). Conclusion: This study characterized the reporting of pulmonary haemorrhage and haemoptysis, along with the time to onset and demographic characteristics among different BV-related treatment options. It could provide valuable evidence for further studies and clinical practice of BV.

Regulatory T cell-derived exosome mediated macrophages polarization for osteogenic differentiation in fracture repair.

Refractory fracture presents an intractable challenge in trauma treatment. Selective polarization of macrophages as well as the recruitment of osteogenic precursor cells play key roles in osteogenic differentiation during fracture healing. Here we constructed regulatory T cell (Treg)-derived exosomes (Treg-Exo) for the treatment of fracture. The obtained exosomes displayed a spheroid shape with a hydrated particle size of approximately 130 nm. With further purification using CD39 and CD73 antibody-modified microfluidic chips, CD39 and CD73 specifically expressing exosomes were obtained. This kind of Treg-Exo utilized the ectonucleotidases of CD39 and CD73 to catalyze the high level of ATP in the fracture area into adenosine. The generated adenosine further promoted the selective polarization of macrophages. When interacting with mesenchymal stem cells (MSCs, osteogenic precursor cells), both Treg-Exo and Treg-Exo primed macrophages facilitated the proliferation and differentiation of MSCs. After administration in vivo, Treg-Exo effectively promoted fracture healing compared with conventional T cell-derived exosome. To further improve the delivery efficacy of exosomes and integrate multiple biological processes of fracture healing, an injectable hydrogel was fabricated to co-deliver Treg-Exo and stromal cell-derived factor 1 alpha (SDF-1α). With the dual effect of Treg-Exo for macrophage polarization and SDF-1α for MSC recruitment, the multifunctional hydrogel exerted a synergistic effect on fracture repair acceleration. This study provided a promising therapeutic candidate and synergistic strategy for the clinical treatment of fracture.

Treatment-related adverse events associated with HER2-Targeted antibody-drug conjugates in clinical trials: a systematic review and meta-analysis.

Background: Given the increasing use of HER2-targeted antibody-drug conjugates (ADCs) worldwide, the summary of toxicity incidence and profiles of these drugs is crucial to provide reference for clinical application. This meta-analysis aimed to estimate the mean incidences of treatment-related adverse events of HER2-targeted ADCs and to investigate the differences between different drugs and cancer types. Methods: We performed a systematic search of literature in PubMed, Embase, Web of Science, and Scopus databases from inception to February 1, 2022 and the last search was updated to August 1, 2022. Published prospective clinical trials on single-agent of the US Food and Drug Administration approved HER2-targeted ADCs with available count data regarding treatment-related adverse events were included. The primary outcomes were pooled incidences of treatment-related adverse events and differences between different drugs and cancer types. The data synthesis was performed using a Bayesian hierarchical modelling method and the protocol was registered in PROSPERO (CRD42022331627). Findings: A total of 39 studies (37 trials) involving 7688 patients across five cancer types were included in the final analysis. On pooling the data using Bayesian hierarchical modelling, the overall mean incidence of all-grade adverse events, high-grade adverse events, serious adverse events, and adverse events that resulted in drug discontinuation were 98.29% (95% CrI, 97.33%-99.07%, τ = 1.49), 47.88% (95% CrI, 42.74%-53.17%, τ = 0.37), 19.45% (95% CrI, 15.70%-23.67%, τ = 0.55), and 10.52% (95% CrI, 8.03%-13.21%, τ = 0.56), respectively. The most common all-grade adverse events were nausea (41.57%; 95% CrI, 40.46%-42.64%, τ = 0.81), fatigue (35.86%; 95% CrI, 34.85%-36.96%, τ = 0.65), and decreased appetite (28.84%; 95% CrI, 22.93%-36.87%, τ = 0.76). The most common high-grade adverse events were thrombocytopenia (8.37%; 95% CrI, 7.75%-9.07%, τ = 0.71), anaemia (6.49%; 95% CrI, 5.86%-7.11%, τ = 1.06), and neutropenia (6.42%; 95% CrI, 5.76%-7.04%, τ = 1.21). We found no difference in the mean incidences of adverse events among different cancer types, as well as different dosing regimens. However, trastuzumab deruxtecan (T-DXd) appeared to have higher mean incidences of adverse events compared with trastuzumab emtansine (T-DM1), especially for the higher dose of T-DXd (6.4 mg/kg Q3W). Interpretation: The incidences of adverse events between two HER2-targeted ADCs were similar in different cancer types, but different HER2-targeted ADCs appeared to have different mean incidences of adverse events. The comprehensive summary of the adverse events of HER2-targeted ADCs is critical for clinicians caring for patients with cancer receiving HER2-targeted ADCs therapy. Funding: The National Natural Science Foundation of China (Grant No. 82073402) and Key R&D Plan of Hubei Province, China (No.2020BCA060) funded this study.

Corrigendum to "Treatment-related adverse events associated with HER2-Targeted antibody-drug conjugates in clinical trials: a systematic review and meta-analysis" [EClinicalMedicine 55 (2022) 101795].

[This corrects the article DOI: 10.1016/j.eclinm.2023.101904.][This corrects the article DOI: 10.1016/j.eclinm.2022.101795.].

Gender differences in adverse events related to Osimertinib: a real-world pharmacovigilance analysis of FDA adverse event reporting system.

OBJECTIVE: We analyze and identify the signals of gender differences in adverse events (ADEs) related to Osimertinib and provide reference for clinical implementation of individualized drug use. METHODS: ADE reports of Osimertinib received from FAERS database from the first quarter of 2016 to the fourth quarter of 2022 were extracted. Reporting odds ratio (ROR) data analysis strategy was used for mining of signal strength that represents gender differences in ADEs related to Osimertinib. RESULTS: The number of Osimertinib ADE reports included in the analysis was 7968 in females and 7570 in males, respectively. According to ROR, men were more likely to develop pneumonia aspiration, lung infection, interstitial lung disease, pulmonary toxicity, dyspnea, ventricular extrasystoles, and pulmonary thrombosis, while women were more likely to develop cardiac failure congestive, stomatitis, diarrhea, muscle spasms, nail disorder, onycholysis, skin disorder, dry skin, and rash. CONCLUSION: Gender differences existed in ADE signals related to Osimertinib. The higher risk of ADEs in male patients was lung diseases that seem more serious than those nail toxicities or skin problems that occurred in female patients. In order to ensure the safety of medication, we should be alert to the differences between different genders and take corresponding preventive measures to reduce the occurrence of serious ADEs.